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The Journal of Neuroscience, August 15, 2002, 22(16):6991-7005
Signaling of Layer 1 and Whisker-Evoked Ca2+ and
Na+ Action Potentials in Distal and Terminal Dendrites of
Rat Neocortical Pyramidal Neurons In Vitro and In
Vivo
Matthew E.
Larkum1 and
J. Julius
Zhu1, 2, 3
1 Department of Cell Physiology, Max Planck Institute
for Medical Research, Heidelberg D-69120, Germany, 2 Cold
Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, and
3 Department of Pharmacology, University of Virginia School
of Medicine, Charlottesville, Virginia 22908
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ABSTRACT |
Dendritic regenerative potentials play an important role in
integrating and amplifying synaptic inputs. To understand how distal
synaptic inputs are integrated and amplified, we made multiple simultaneous (double, triple, or quadruple) and sequential (4-12 paired) recordings from different locations of single tufted layer 5 pyramidal neurons in the cortex in vitro and studied the
spatial and temporal properties of their dendritic regenerative
potential initial zone. Recordings from the soma and from trunk,
primary, secondary, tertiary, and quaternary tuft branches of the
apical dendrite of these neurons reveal a spatially restricted
low-threshold zone ~550-900 µm from the soma for
Ca2+-dependent regenerative potentials. Dendritic
regenerative potentials initiated in this zone have a clearly defined
threshold and a refractory period, and they can propagate actively
along the dendrite before evoking somatic action potentials. The
detailed biophysical characterization of this dendritic action
potential initiation zone allowed for the further investigation of
dendritic potentials in the intact brain and their roles in information
processing. By making whole-cell recordings from the soma and varied
locations along the apical dendrite of 53 morphologically identified
layer 5 pyramidal neurons in anesthetized rats, we found that three of
the dendritic potentials characterized in vitro could be
induced by spontaneous or whisker inputs in vivo. Thus
layer 5 pyramidal neurons of the rat neocortex have a spatially
restricted low-threshold zone in the apical dendrite, the activation or
interaction of which with the axonal action potential initiation zone
is responsible for multiple forms of regenerative potentials critical
for integrating and amplifying sensory and modulatory inputs.
Key words:
rat; somatosensory; excitation; inhibition; synaptic
integration; development; attention; synaptic plasticity
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INTRODUCTION |
In 1951, Chang recorded a slow
potential in the neocortex and proposed that the apical dendrite of
pyramidal neurons can support regenerative potentials (Chang, 1951a ,b).
This proposal remained contentious for decades in the absence of direct
intracellular recordings from the apical dendrite (Bishop and Clare,
1953; Purpura and Grundfest, 1956). More recent work confirms the
existence of active conductances in the apical dendrite of pyramidal
neurons (Spencer and Kandel, 1961; Wong et al., 1979; Benardo et al., 1982; Turner et al., 1991; Amitai et al., 1993; Kim and Connors, 1993;
Regehr et al., 1993; Magee and Johnston, 1995a; Schwindt and Crill,
1995; Golding and Spruston, 1998). It is now clear that
Ca2+-dependent regenerative potentials can
be initiated in the distal apical dendrite of pyramidal neurons
(Schiller et al., 1997; Golding et al., 1999; Zhu, 2000; Oakley et al.,
2001). Initiation of dendritic regenerative potentials can have
profound effects on synaptic integration and synaptic plasticity (for
review, see Hausser et al., 2000; Magee, 2000; Reyes, 2001). However,
the threshold for activation of Ca2+
potentials, its time-dependent properties, and the spatial extent of
the dendritic initiation zone remained to be elucidated.
Using multiple simultaneous and sequential recordings from the soma and
different locations of the apical dendrite of single layer 5 pyramidal
neurons of adult rats [more than postnatal day 42 (P42)], we mapped
the electrical excitability of the apical dendrite. We found that adult
layer 5 pyramidal neurons have a low-threshold zone in the distal
apical dendrite for initiating predominantly
Ca2+-dependent regenerative potentials.
The regenerative dendritic potentials had a threshold and a refractory
period and could propagate without decrement along the apical dendrite.
The results indicate that adult layer 5 pyramidal cells have an
additional site for amplification and integration of synaptic inputs.
The dendritic action potential initiation zone of layer 5 pyramidal
neurons can interact with the axonal action potential initiation zone.
In addition to the dendritically initiated regenerative potentials,
several other regenerative potentials have been observed, and their
biophysical properties have been characterized by previous in
vitro studies (Larkum et al., 1999a,b, 2001; Zhu, 2000). However, dendritic regenerative potentials are much less studied in
vivo; only a small number of dendritic recordings have been made
from the apical dendrite of layer 5 pyramidal neurons in the intact brain (Helmchen et al., 1999; Zhu and Connors, 1999). So far, it is
still unclear whether the multiple forms of regenerative potentials
observed in in vitro preparations occur in vivo.
In this study we made whole-cell recordings from the soma and varied locations along the apical dendrite of layer 5 pyramidal neurons in
anesthetized rats. We found that three of the regenerative potentials
characterized in vitro could be evoked by spontaneous and
whisker inputs. Although some of the biophysical characteristics of the
regenerative potentials remained unchanged in vivo, others were notably different in the intact brain.
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MATERIALS AND METHODS |
In vitro brain slice preparation. Brain slices
of the somatosensory neocortex were prepared from 6- to 8-week-old
(180-280 gm) Wistar rats unless stated otherwise. The main procedure
followed a previous study (Zhu, 2000). In brief, animals were
anesthetized deeply by halothane and decapitated. The brain was
removed quickly and placed into cold (0-4°C) oxygenated
physiological solution containing (in mM): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 25 NaHCO3, 1 MgCl2, 25 dextrose, and 2 CaCl2, pH 7.4. Sagittal slices
250-300 µm thick were cut from the tissue blocks with a microslicer.
These slices were kept at 37.0 ± 0.5°C in oxygenated
physiological solution for ~1 hr before recordings were made. During
the recording the slices were submerged in a chamber and stabilized
with a fine nylon net attached to a platinum ring. The chamber was
perfused with oxygenated physiological solution, the half-time for the bath solution exchange being ~6 sec. As reported previously (Chang, 1952), we found that the initiation and propagation of dendritic regenerative potentials were compromised when neurons were recorded at
room temperature, attributable presumably to the high sensitivity of
calcium channel kinetics to the temperature (Coulter et al., 1989;
McAllister-Williams and Kelly, 1995). Thus all recordings reported in
this study were performed with the temperature of the bath solution in
the recording chamber maintained at 35.0 ± 0.5°C. All
antagonists were bath applied.
In vitro electrophysiology. Double, triple, quadruple,
and multiple recordings were made on single identified layer 5 pyramidal neurons by using infrared illumination combined with
differential interference contrast optics. Somatic (5-10 M ) and
dendritic (10-25 M) recording pipettes were filled with standard
intracellular solution containing (in mM): 115 potassium
gluconate, 10 HEPES, 2 MgCl2, 2 Mg-ATP, 2 Na2ATP, 0.3 GTP, and 20 KCl plus 0.25% biocytin, pH 7.3. Dendritic tufts branches were identified and recorded as
described previously (Zhu, 2000). Whole-cell recordings were made with
up to four Axoclamp-2B amplifiers (Axon Instruments, Foster City, CA).
Whenever necessary, the output of recording head stages was monitored
on an oscilloscope so that the electrode capacitance compensation could
be made in the discontinuous current-clamp mode. A 10 mV liquid
junction potential was subtracted from all membrane potentials.
In vitro synaptic stimulation. Extracellular synaptic
stimulation was made by a concentric bipolar electrode with single
voltage pulses (200 µsec, up to 40 V, 0.25 Hz). The stimulating
electrode was placed at the border of layer 1 and layer 2, ~1200-1500 µm lateral from the cells that were recorded. Slices
were cut between the stimulating electrode and the cells with a
surgical scraper (from the middle layer 2 to white matter; 300-500
µm lateral from the cells). This arrangement made it possible to
activate layer 1/2 synaptic inputs more selectively (cf. Cauller and
Connors, 1994). Sometimes the stimulating electrode was placed in the
border of layer 6 and white matter, ~100-300 µm lateral from the
cells that were recorded, to activate layer 4/5 inputs of layer 5 pyramidal neurons.
In vivo animal preparation. As described previously
(Zhu and Connors, 1999), 6- to 8-week-old (180-280 gm) Wistar rats
were anesthetized initially by an intraperitoneal injection of
pentobarbital sodium (60 mg/kg). Supplemental doses (10 mg/kg) of
pentobarbital were given as needed to keep animals free from pain
reflexes and in a state of slow-wave general anesthesia, as determined
by monitoring the cortical electroencephalogram (EEG). All pressure
points and incised tissues were infiltrated with lidocaine. Body
temperature (rectal) was monitored and maintained within the normal
range (37.2 ± 0.3°C). During the physiological investigation
the animals were placed in a stereotaxic frame. A hole ~3 × 4 mm was opened above the right somatosensory cortex according to the
stereotaxic coordinates (Chapin and Lin, 1984). The dura was opened
just before the electrode penetrations. Electrodes typically were
arranged to penetrate the barrel cortex at ~60° against the surface
plane, aiming at the center of the mystacial vibrissal barrel cortex. At the end of each neuronal recording the subpial depth of the cell was
estimated from the distance that the micromanipulator had advanced,
taking into account the angle that the electrode formed with the
surface of the barrel cortex. The estimation matched well with the
reconstructed electrode penetration pathway that was revealed after
histology processing (see below).
In vivo electrophysiology. Whole-cell recordings from
the soma and dendrite of cortical neurons were made blindly, as
described in a previous report (Zhu and Connors, 1999). Long-taper
patch electrodes were made from borosilicate tubing, and their
resistances were initially 7-15 M. The same intracellular solution
used in in vitro experiments was used. A 10 mV liquid
junction potential was subtracted from all membrane potentials to
facilitate the comparison of in vitro and in vivo
data. To obtain whole cell recordings, we advanced electrodes
into the brain while pulsing with 0.1 nA current steps of 200 msec
duration. Positive pressure (75-150 mbar) was applied constantly to
the pipette while it was being advanced. Once in a while, a short pulse
of high pressure (300-450 mbar) was applied to inject biocytin and
stain cell debris along the penetration pathway. When a sudden increase
in electrode resistance was evident, gentle suction was applied to
obtain a seal resistance of  1 G. The patch of the membrane was
broken by applying more negative pressure to obtain a whole-cell
configuration. All in vivo data were collected when the
access resistance of recordings was <50 M. An Axoclamp-2B amplifier
(Axon Instruments) was used for intracellular recordings. The electrode
capacitance compensation was made in discontinuous current-clamp mode,
with the head stage output continuously monitored on a second
oscilloscope. A satisfactory capacitance compensation was achieved in
most recordings (with the exception of recordings from the soma and
proximal dendrite of a few layer 5 pyramidal neurons).
In vivo whisker and synaptic stimulation. Single
whiskers on the contralateral face were deflected briefly for a short
distance (40-200 µm) with a piezoelectric stimulator placed adjacent
to the whisker and activated by single brief voltage pulses (0.3-0.5 msec, 2-10 V, 0.25 Hz) (cf. Dykes et al., 1977; Simons, 1983). Extracellular synaptic stimulation was made by a concentric bipolar electrode with single voltage pulses (200 µsec, up to 25 V, 0.25 Hz).
The stimulating electrode was placed on the cortical surface ~1000-2000 µm lateral from the electrode penetration site to
activate layer 1/2 synaptic inputs more selectively (cf. Chang,
1952).
Histology. After in vitro recordings the slices
were fixed by immersion in 4% paraformaldehyde in 0.1 M phosphate buffer. After in vivo
recordings a small block of tissue, including the recorded cell, was
removed from the brain and immersion-fixed with 4% paraformaldehyde in
0.1 M phosphate buffer. Later, the tissue blocks
were sectioned 250 µm thick with a microslicer. Tissue sections from
in vitro and in vivo experiments were processed with the avidin-biotin-peroxidase method to reveal cell morphology. Cells then were drawn with the aid of a microscope equipped with a
computerized reconstruction system (Neurolucida; MicroBrightField, Colchester, VT). Only the data from the morphologically identified layer 5 pyramidal neurons were included in this report. For in vivo experiments, electrode penetration pathways were
reconstructed on the basis of the biocytin staining of cell
debris observed along the electrode penetration tracks (see Figs.
9-11). Then the exact site at the soma or apical dendrite of layer 5 pyramidal neurons at which the recordings were made was determined accordingly.
The threshold of dendritic regenerative potentials was determined by
increasing stimuli with small steps (0.1 nA or 0.2 V). The threshold
potential and duration of regenerative events were measured at their
threshold point. All results are reported as the means ± SEM.
Statistical differences of the means were determined by using paired
Student's t test unless stated otherwise. The level of
significance was set at p < 0.05.
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RESULTS |
Initiation of regular and burst patterns of action potentials in
thick-tufted L5 neurons
With dual and triple whole-cell voltage recordings made from the
same neuron (Fig. 1A)
and depending on where in the neurons the dendritic current was
injected, two major types of action potential patterns were evoked
after (relatively long, 500 msec) rectangular current injections.
Suprathreshold dendritic current injection always generated a
regenerative potential in the dendrite and a burst of somatic
Na+ action potentials in the soma, whereas
prolonged somatic current injection evoked action potentials occurring
in either a burst pattern (n = 21) or a regular pattern
(n = 22) in the soma. Figure 1B,C
shows an example from a regular-spiking cell with somatic-injected current (RS; for definition, see Connors and Gutnick, 1990). The neuron
responded to dendritic current injection with a burst of Na+ action potentials (Fig.
1B), whereas somatic current injection caused a tonic
firing of Na+ action potentials (Fig.
1C) (cf. Wong and Stewart, 1992; Schwindt and Crill,
1998).
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Figure 1.
Burst and regular patterns of axonal action
potentials evoked in the same neurons depend on the site of current
injection. A, Reconstruction of a thick-tufted L5
pyramidal neuron. The schematic drawing of recording pipettes indicates
the locations of the dendritic (908 and 868 µm distal from the soma
for P3 and P2, respectively) and somatic
recordings. The length of the apical dendrite was 1279 µm.
B, "Burst-like" axonally induced action potential
pattern after dendritic current injection in the neuron, recorded with
somatic pipette. The dendritic pipette recorded a
Ca2+-dependent regenerative potential.
C, "Regular" axonal action potential pattern after
somatic current injection in the same neuron, recorded with somatic
pipette. The dendritic pipette recorded an attenuated pattern of
somatic action potentials. Note that the top traces show
dendritic responses, whereas the bottom traces show
somatic responses (similarly in the following figures). The resting
membrane potentials at the very distal dendrite, proximal distal
dendrite, and soma were  72, 73, and 76 mV, respectively.
D, Burst-like axonally induced action potential pattern
after dendritic current injection in another neuron, recorded with
somatic pipette. The locations of the dendritic recordings were 573 and
504 µm distal from the soma for P3 and
P2, respectively. The length of the apical dendrite was
1220 µm. E, Bath application of 50 µM
Cd2+ transformed the burst firing pattern in the
soma into the regular firing pattern. Dendritic recording traces are
not shown in D and E. The resting
membrane potentials at the very distal dendrite, proximal distal
dendrite, and soma were 73, 75, and 81 mV, respectively.
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The difference between the patterns of somatic action potentials evoked
by somatic and dendritic current injections was reduced or abolished in
the presence of 50 µM Cd2+,
a blocker of Ca2+ channels
(n = 4) (Fig. 1D,E, respectively).
This result suggests that Ca2+ conductance
can play a crucial role in the generation of bursts of action
potentials at the soma and is consistent with our previous finding that
the activation of dendritic Ca2+-dependent
regenerative potentials can dominate the output discharge pattern of
the neuron (Zhu, 2000; Larkum et al., 2001). To understand exactly what
mechanisms led to this dendritic influence, we investigated in more
detail the biophysical properties of this initiation zone in the distal
dendrite underlying the Ca2+-dependent
regenerative potential by using multiple simultaneous and sequential
recordings along the apical dendrite and the soma. Our main goals were
to characterize the potentials generated in this region by using the
classical descriptive parameters for action potentials in all neurons:
major ion conductances, threshold, refractory period, and propagation,
which are crucial for us to understand how distal synaptic inputs are integrated.
Temporal properties of dendritic action potential
initiation zone
When a relatively short (50 msec) step-depolarizing current pulse
was injected into one of the tuft branches (Fig.
2A), it invariably
evoked a slow regenerative potential with several peaks and dips that
was mediated mainly by a Ca2+ conductance
(Schiller et al., 1997; Zhu, 2000; Larkum et al., 2001). Concomitant
with the dendritic regenerative potential, two to four
Na+ action potentials were recorded at the
somatic pipette. Characteristically, the dendritic potential preceded
the first somatic action potential in a burst, and all somatic action
potentials propagated back into the dendritic arbor to induce
depolarizing peaks riding on the top of the dendritic regenerative
potential. Unlike P28-P32 neurons (Schiller et al., 1997; Zhu, 2000),
rectangular current pulse (50 msec) injection evoked both dendritic
regenerative potentials and somatic action potentials in adult neurons
even at threshold. Dendritic potentials were initiated in an
all-or-none manner with a clear threshold, and they overshot 0 mV
(n = 35) (Fig. 2B). Dendritic
regenerative potentials lasted much longer than
Na+ action potentials and ranged from 30 to 80 msec with a mean duration of 56.5 ± 12.6 msec
(n = 35). The duration of dendritic potentials was not
correlated with the number of
Na+-dependent action potentials recorded
in the soma (2-4 action potentials; r = 0.097; ANOVA;
p > 0.5).
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Figure 2.
Duration and refractory period of regenerative
potentials in the apical dendritic tuft neurons evoked by current pulse
injection. A, Reconstruction of a biocytin-stained
pyramidal neuron. The schematic drawing of recording pipettes indicates
the location of the dendritic (981 µm distal from the soma; secondary
tufts) and somatic recordings. The length of the apical dendrite was
1387 µm. B, All-or-none regenerative potentials evoked
by depolarizing current injections into the dendrite of neuron.
C, Paired depolarizing current injections at the
dendritic electrode separated by varying time periods indicating the
refractory period of dendritic regenerative potentials. The recordings
with the altered regenerative potential are shown separated in
D. E, Increasing the intensity of the
second current pulse could evoke the regenerative potentials at a
higher threshold. The calibration applies in B-E.
F, Plotting threshold for the second regenerative
potential against the interval between the two pulses revealed the
refractory period of regenerative potentials. The data
points were obtained from seven different neurons and were fit
arbitrarily by an inverse function. The resting membrane potentials at
the soma and dendrite were 78 and 69 mV, respectively.
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Dendritic regenerative potentials, when evoked by current injection (50 msec at threshold intensity), had a relatively long refractory period.
Paired pulse injection with varying interpulse intervals showed that
the second depolarizing current pulse (50 msec) failed to evoke a
regenerative potential if the interval between the two pulses was too
short, the relative refractory period being ~250 msec (Fig.
2C,F). During the relative refractory period the time
course of dendritic potentials was altered, and the leading peak
appeared not to be fully regenerative, although a burst of
Na+ action potentials still could be
evoked, followed by the typical plateau-like dendritic potential (Fig.
2D). The duration of the refractory period decreased
with increasing amplitude of the depolarizing current (Fig.
2E,F), the absolute refractory period under
these conditions being ~50 msec (n = 7) (Fig.
2F).
Spatial properties of dendritic action potential
initiation zone
To map the spatial extent of excitability in the distal dendrites,
we made multiple sequential recordings from different locations along
the apical dendrite. A second pipette recording was always placed at
the soma of the same pyramidal neuron (8-12 sequential paired
recordings, n = 4; 4-7 sequential paired recordings,
n = 4) (Fig.
3A). We found that a short (50 msec) current pulse injection into the proximal dendritic trunk
initiated action potentials first at the soma (data not shown). Current
pulse injections into the middle portion of the apical dendritic trunk
showed that the initiation of regenerative potentials depended on the
intensity of stimulation. At threshold, the somatic action potential
preceded the dendritic regenerative potential (Fig. 3B).
Suprathreshold stimulation evoked a
Ca2+-dependent dendritic regenerative
potential and a burst of axonal action potentials. The leading
depolarization of the dendritic potential preceded the somatic action
potential (Fig. 3C). The results are consistent with the
previous studies (Stuart and Sakmann, 1994; Stuart et al., 1997)
(see also Chen et al., 1997). Finally, when current was injected into
the distal dendritic trunk (686 ± 62 µm distal to the soma;
n = 8) or in the primary or in the secondary dendritic
tufts, a Ca2+-dependent dendritic
regenerative potential was initiated at threshold concomitant with a
burst of somatic action potentials (Fig. 3D).
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Figure 3.
Thresholds of regenerative potentials along the
apical dendrite. A, Schematic drawing of the recording
pipettes indicates the locations of the dendritic (1055, 954, 801, 753, 655, 600, 564, 527, 482, 336, and 214 µm distal from the soma) and
somatic recordings in 11 dual recordings from the same cell. Note that
the dendritic recordings were obtained in random order. The length of
the apical dendrite was 1367 µm. B, Somatic action
potentials started earlier than the dendritic regenerative potentials
in response to the threshold current injection at the dendrite 655 µm
from the soma. C, At a higher current intensity the
dendritic regenerative potentials were elicited before the somatic
action potentials. D, At 954 µm from the soma the
dendritic regenerative potentials always started first. The calibration
applies to B-D. E, Plots of thresholds
for somatic action potentials (filled circles)
and for dendritic regenerative potentials (in the cases in which the
dendritic potentials preceded the somatic action potentials;
open squares) as a function of distance from the soma.
The resting membrane potential at the soma was 78 mV. A regression
line is fit to the somatic thresholds. The resting membrane potentials
at the dendrite from distal to proximal were 69, 69, 70, 74,
75, 76, 77, 78, 78, 78, and 78 mV, respectively.
F, G, Plots of threshold for dendritic regenerative
potentials (F) or input resistance
(G) at the different locations of the dendrites
of eight different neurons as a function of distance from the
soma.
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The threshold intensity for the initiation of regenerative dendritic
potentials showed a progressive decrease in the distal dendrite and a
progressive increase for somatic action potential initiation as a
function of distance from the soma (Fig. 3E-G). These
results indicate that, in the apical dendrites close to the bifurcation
region of layer 5 pyramidal neurons with typical dendritic morphology,
the threshold for the initiation of a dendritic regenerative potential
is lower than that for the initiation of an axonal action potential.
Active propagation and spread of dendritic
regenerative potentials
To determine how far regenerative potentials actively travel along
the apical dendrite, we made simultaneous dendritic recordings in the
dendritic tuft and distal dendritic trunk. Because the low-threshold
region extended over a length estimated to be ~200-400 µm (Fig.
3E,F), we tested how a dendritic regenerative
potential, once initiated, traveled within this region toward the soma.
For this we made triple or quadruple recordings from the apical
dendrite and soma (Fig. 4). The distal
dendritic pipette was used to elicit and to record the dendritic
depolarizing potentials in the dendritic tuft, whereas the proximal
dendritic pipette or pipettes were used to measure the degree of
attenuation of the dendritic depolarizing potentials in the distal
dendritic trunk.
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Figure 4.
Propagation and spread of regenerative potentials
along the apical dendrite. A, Schematic drawing of
recording pipettes indicates the locations of the dendritic (809, 657, and 338 µm distal from the soma) and somatic recordings in two triple
recordings from the same cell. The length of the apical dendrite was
1232 µm. B, Responses in the dendritic tufts (809 µm), distal dendritic trunk (657 µm), and soma to step-depolarizing
current injections at the tufts of the same neuron. Note that the
regenerative potential began first in the primary tufts, propagated to
the distal dendritic trunk with little attenuation in amplitude, and
was followed by the somatic action potentials. C,
Threshold for dendritic regenerative potentials evoked by current
injection in the primary tufts or distal trunks. D,
Amplitude of dendritic regenerative potentials in the primary tufts and
distal trunks in response to current injection in the primary tufts.
E, Responses of the dendritic tufts (809 µm), proximal
dendritic trunk (338 µm), and soma to step-depolarizing current
injections at the tufts of the same neuron. Note that the regenerative
potential started first in the primary tufts, propagated to the
proximal dendritic trunk with intermediate attenuation in amplitude,
and was followed by the somatic action potentials. The full-amplitude
regenerative potentials in the proximal trunk were generated after the
somatic action potentials. The resting membrane potential at the soma
was 79 mV. The resting membrane potentials at the dendrite from
distal to proximal were 68, 68, and 77 mV, respectively.
F, Responses in a secondary dendritic tuft branch
(P2; 869 µm), a primary dendritic tuft branch
(P3; 706 µm), the proximal dendritic trunk
(P4; 225 µm), and soma (P1) to
step-depolarizing current injections at the distal tuft branch of
another neuron. Note that the regenerative potential began first in the
secondary tuft, propagated to the primary tuft with little attenuation
in amplitude, and was followed by the full-amplitude regenerative
action potentials first in the proximal dendrite and then in the soma.
The resting membrane potential at the soma was 80 mV. The resting
membrane potentials at the dendrite from distal to proximal were 68,
69, and 75 mV, respectively. The calibration applies to B,
E, F.
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The thresholds for initiating the
Ca2+-dependent dendritic regenerative
potentials in the primary tuft (699 ± 24 µm; n = 7) and distal dendritic trunk (588 ± 23 µm; n = 7) were the same (48.7 ± 1.6 vs 48.0 ± 1.9 mV;
n = 7; p = 0.65) (Fig.
4B,C). During the forward propagation from the
primary tuft to distal dendritic trunk, the amplitude of regenerative
potentials changed little (76.0 ± 2.3 vs 73.1 ± 1.6 mV;
n = 7; p = 0.13) (Fig.
4D). These results are consistent with the presence
of an extended low-threshold zone around the main branch point for the
initiation of dendritic regenerative potentials (Fig.
3E,F). Propagation of the dendritic potentials in the
proximal trunk was more variable. In some layer 5 pyramidal neurons the
dendritic regenerative potentials transformed into graded potentials in
the proximal trunk, which still could produce somatic action potentials
(Fig. 4E). In other neurons they actively propagated
into the proximal trunk, particularly when they were depolarized (Fig.
4F) (see also Larkum et al., 2001).
The threshold for the initiation of regenerative potentials appeared to
increase toward the distal dendritic tips (Fig.
3E,F). To examine the distal extent of the active
dendritic zone and to study the initiation and propagation of
regenerative potentials in the terminal dendrite, we made dual
simultaneous recordings from the primary (n = 7) and
tertiary (n = 5) or quaternary (n = 2)
tuft branches of the same pyramidal neurons (Fig.
5A). The average distance of
the recordings at the primary tufts from the soma was 764 ± 22 µm (n = 7), whereas that of the recordings at the
tertiary and quaternary tufts was 939 ± 32 µm
(n = 7). The resting membrane potential in the tertiary
and quaternary tufts was more depolarized than that in the primary
tufts (66.4 ± 1.2 vs 70.6 ± 0.6 mV; n = 7; p < 0.005). The tertiary and quaternary tufts also
had a higher input resistance than the primary tufts (26.9 ± 1.8 vs 13.7 ± 1.3 M; n = 7; p < 0.0005). The membranes of tertiary and quaternary tufts were less
excitable; the depolarization required to evoke a regenerative
potential in the tertiary or quaternary tufts was significantly higher
than that in the primary tufts (26.7 ± 3.6 vs 46.6 ± 1.4 mV; n = 7; p < 0.001) (Fig. 5B,D). Consistent with this observation, we found that,
regardless of the pipette through which the depolarizing current was
injected, the Ca2+-dependent dendritic
regenerative potentials always were initiated first at the primary
tufts and then propagated to the tertiary and quaternary tufts
(n = 7) (Fig. 5C). During the backward
propagation from the primary tufts to the tertiary and quaternary
tufts, the amplitude of the regenerative potentials was attenuated by
~25% (81.7 ± 0.6 vs 61.6 ± 3.7 mV; n = 7; p < 0.005) (Fig. 5B,E). The results thus
indicate a low-threshold zone at the bifurcation region for the
initiation of regenerative potentials, which propagate both toward the
soma and away from the soma into the distal dendritic tips.
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Figure 5.
Initiation of the dendritic regenerative
potentials in the apical dendritic tuft. A, The
schematic drawing of recording pipettes indicates the locations of the
dendritic recordings (867 and 1080 µm distal from the soma; primary
and tertiary tufts, respectively). The length of the apical dendrite
was 1210 µm. B, Responses to the step current
injection in the primary or tertiary tufts. The suprathreshold
recording traces are expanded and superimposed in C to
show that the regenerative potentials always started earlier in the
primary tufts. Note that the top traces show the
responses in the tertiary tufts, whereas the bottom traces show the
responses in the primary tufts. The resting membrane potentials at the
primary and tertiary dendritic tufts were 68 and 62 mV,
respectively. The calibration applies to both B and
C. D, Threshold for dendritic
regenerative potentials evoked by current injection in the primary and
tertiary or quaternary tufts. E, Amplitude for
dendritic regenerative potentials in the primary and tertiary or
quaternary tufts in response to current injection in the primary
tufts.
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Initiation of dendritic regenerative potentials by layer 1 synaptic
stimulation in vitro
Initiation of dendritic regenerative potentials depends strongly
on the size and time course of the current injected in the dendrite
(Larkum et al., 2001). It was therefore important to know what kind of
dendritic potentials might be generated by synaptically evoked inputs,
which differ from injected current in many aspects, including size and
time course. We evoked synaptic inputs in layer 5 pyramidal neurons by
extracellular stimulation. Extracellular stimulation of afferent fibers
in layer 1 could evoke a Ca2+-dependent
dendritic potential followed by a burst of action potentials in the
soma (n = 16) (Fig. 6).
In younger (P14-P28) pyramidal cells, dendritically initiated
regenerative potentials at threshold intensity were restricted mostly
to the dendritic tufts, and it was only after higher-than-threshold
stimulation intensity that the dendritic depolarization preceded the
burst of somatic action potentials (Schiller et al., 1997; Zhu, 2000).
We ruled out any washout effects of whole-cell recording that might
cause an altered excitability by synaptic stimulation in layer 1 by
recording dendritic and somatic potentials first in a cell-attached
configuration (n = 5). Stimulation within layer 1 evoked large dendritic EPSPs in the tufts, whereas the depolarization
at the soma was strongly attenuated (Fig. 6B).
Increasing stimulation intensity eventually evoked a regenerative
potential in the distal tuft dendrites and simultaneously a burst of
two to three Na+ action potentials at the
soma (Fig. 6B,C). Subsequent whole-cell intracellular
voltage recordings at the same dendritic and somatic locations
confirmed that the synaptic stimulation evoked a
Ca2+-dependent regenerative potential in
the dendritic tufts and a burst of action potentials in the soma (Fig.
6D,E), indicating that the whole-cell configuration
did not alter the regenerative properties of the dendrite in these
respects.
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Figure 6.
Layer 1 stimulation-evoked regenerative potentials
in apical dendritic tuft. A, Schematic drawing of the
preparation used to stimulate layer 1 input selectively (similarly in
Fig. 7). The location of the dendritic recording was 1044 µm from the
soma. The length of the apical dendrite was 1333 µm.
B, Extracellular cell-attached recordings showed that
synaptic stimulation-evoked regenerative potentials in the tufts
started earlier than somatic action potentials. C,
Average extracellular peak voltage responses (two trials) at the
dendritic tufts and soma are plotted as a function of stimulation
intensity. D, Intracellular recordings showed that
regenerative potentials in the tufts started earlier than somatic
action potentials. E, Average intracellular peak voltage
responses (two trials) at the dendritic tufts and soma are plotted as a
function of stimulation intensity. The calibration applies to
B and D. The resting membrane potentials
at the soma and dendrite were 80 and 74 mV, respectively.
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The Ca2+-dependent dendritic regenerative
potentials evoked by synaptic stimulation were shorter than those
evoked by current injection. On average, the duration of the
synaptically evoked dendritic potentials recorded intracellularly was
19.8 ± 0.6 msec (n = 16), more comparable with
those evoked by spontaneous and synaptic inputs in anesthetized animals
in vivo (see below; Chang, 1951a; Bishop and Clare, 1953;
Purpura and Grundfest, 1956; Zhu and Sakmann, 1998). By depolarizing
the membrane potential in the dendrite, we found that the synaptic
stimulation-evoked EPSP was followed by a slow inhibitory postsynaptic
potential (Fig. 7A,B), which
curtailed the duration of synaptically evoked dendritic potentials. The
reversal potential of the slow potential, estimated by plotting its
amplitude against the membrane potential, was 56.4 ± 2.9 mV
(n = 4) (Fig. 7B,C), more depolarizing than
the resting membrane potentials (cf. Zhu and Connors, 1999). These results suggest that the slow potential is generated by GABAergic inputs (Larkum et al., 1999a; Zhu and Connors, 1999; Porter et al.,
2001), and it may contribute to the initial depolarization of the
membrane potential and initiation of dendritic regenerative potentials.
The peaks and dips of the dendritic regenerative potentials evoked by
synaptic stimulation, representing back-propagating Na+ action potentials initiated in the
axon, were less evident. This is consistent with coactivation of
disynaptic inhibitory potentials and a large increase in membrane
conductance.
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Figure 7.
Layer 1 stimulation-evoked IPSP in apical
dendritic tuft. A, The schematic drawing of recording
pipettes indicates that the location of the dendritic recording was 914 µm from the soma. The length of the apical dendrite was 1300 µm.
B, Intracellular recordings show the layer 1 stimulation-evoked EPSP and IPSP in the soma and tuft at different
membrane potentials. The membrane potentials were altered by the
injection of continuous depolarizing currents via the recording pipette
in the tuft. C, Plot of amplitude of EPSP and IPSP
against membrane potential in the tuft. The resting membrane potentials
at the soma and dendrite were 74 and 70 mV, respectively.
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Initiation of dendritic regenerative potentials by synaptic
stimulation of deep layers in vitro
Previous study has shown that back-propagating bursts of
Na+ action potentials induced by somatic
current injections can evoke dendritic regenerative potentials (Larkum
et al., 2001). We wished to know whether layer 4/5 synaptic inputs also
could evoke bursts of somatic action potentials and, subsequently,
regenerative potentials in the dendrite of layer 5 pyramidal neurons.
Thus we made simultaneous recordings from layer 5 pyramidal neurons at
the soma and tuft and examined their responses to the synaptic
stimulation of layer 6. Unlike younger P14 neurons, which always
responded to a suprathreshold somatic current injection with a single
Na+ action potential in the soma and a
large back-propagating Na+ action
potential in the dendrite (Fig.
8A) (Stuart and
Sakmann, 1994; Zhu, 2000), adult layer 5 pyramidal neurons responded to a suprathreshold somatic current injection with two different firing
modes (Fig. 8B,C). Approximately one-half of them (22 of 43) responded with a single Na+ action
potential in the soma, which was followed by a small back-propagating Na+ action potential in the dendrite,
whereas the other one-half (21 of 43) responded with a burst of
Na+ action potentials at the soma, which
was followed by a large Ca2+-dependent
regenerative potential in the dendrite. These results are consistent
with the ideas that two populations [regular spiking (RS) and
intrinsically bursting (IB) neurons (see Connors and Gutnick, 1990)]
of large layer 5 pyramidal neurons exist in the adult neocortex and
that they develop from a single population of young RS neurons
(Franceschetti et al., 1998).
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Figure 8.
Synaptic stimulation-evoked regenerative
potentials in apical dendritic tuft. A, Reconstruction
of a biocytin-stained P14 pyramidal neuron. The schematic drawing of
recording pipettes indicates the location of the dendritic (697 µm
distal from the soma; secondary tufts) and somatic recordings. The
length of the apical dendrite was 1002 µm. Threshold current
injection into the soma induced a single action potential in the soma
and a large, fast action potential in the tufts. The resting membrane
potentials in the soma and dendrite were 66 and 68 mV,
respectively. B, Reconstruction of a biocytin-stained RS
pyramidal neuron. The schematic drawing of recording pipettes indicates
the location of the dendritic (987 µm distal from the soma; secondary
tufts) and somatic recordings. The length of the apical dendrite was
1469 µm. Threshold current injection into the soma induced a single
action potential in the soma and a small, fast action potential in the
tufts. The resting membrane potentials in the soma and dendrite were
69 and 76 mV, respectively. C, Reconstruction of a
biocytin-stained IB pyramidal neuron. The schematic drawing of
recording pipettes indicates the location of the dendritic (757 µm
distal from the soma; secondary tufts) and somatic recordings. The
length of the apical dendrite was 1222 µm. Threshold current
injection into the soma induced a burst of action potentials in the
soma and a large, slow action potential in the tufts. The resting
membrane potentials in the soma and dendrite were 74 and 84 mV,
respectively. D, Sholl analysis of dendritic branch
patterns of P14 cells, RS cells, and IB neurons in layer 5. E, Top traces, A long current step
injection induced repetitive action potentials in the soma and small,
fast action potentials in the tufts in a RS neuron. Note that the
amplitude of the fast action potentials in the tufts was reduced
progressively. Bottom traces, Increasing the current
intensity induced a burst of action potentials at the onset of in the
response in the soma, which was followed by a large, slow calcium
action potential in the tufts. The dendritic recording was 716 µm
distal from the soma. The length of the apical dendrite was 1160 µm.
The resting membrane potentials in the soma and dendrite were 60 and
81 mV, respectively. F, Top traces, A
long current injection induced repetitive bursts in the soma and large,
slow action potentials in the tufts in an IB neuron. Bottom
traces, Increasing the current intensity transformed the later
bursts into tonic-like firing, which was followed by small, fast action
potentials in the tufts. Note that the amplitude of the fast action
potentials in the tufts was reduced progressively. The dendritic
recording was 870 µm distal from the soma. The length of the apical
dendrite was 1231 µm. The resting membrane potentials in the soma and
dendrite were 72 and 79 mV, respectively. G,
Threshold and suprathreshold synaptic stimulation induced single action
potentials in the soma and single large, fast action potentials in the
tufts of a P14 cell. The dendritic recording was 590 µm distal from
the soma. The length of the apical dendrite was 989 µm. The resting
membrane potentials of the cell in the soma and dendrite were 72 and
75 mV, respectively. H, Threshold synaptic stimulation
induced a single action potential in the soma and a small, fast action
potential in the tufts of a RS cell. Suprathreshold synaptic
stimulation induced a burst of action potentials in the soma and a
large, slow action potential in the tufts of the RS cell. The dendritic
recording was 907 µm distal from the soma. The length of the apical
dendrite was 1420 µm. The resting membrane potentials of the cell in
the soma and dendrite were 72 and 78 mV, respectively.
I, Threshold synaptic stimulation induced a burst of
action potentials in the soma and a large, slow action potential in the
tufts of an IB cell. Suprathreshold synaptic stimulation induced a
single action potential in the soma and a small, fast action potential
in the tufts of the IB cell. The dendritic recording was 870 µm
distal from the soma. The length of the apical dendrite was 1247 µm.
The resting membrane potentials of the cell in the soma and dendrite
were 71 and 77 mV, respectively.
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Although RS and IB cells fired action potentials in different modes,
they had the same resting membrane potential (77.4 ± 0.6 mV,
n = 17 vs 77.2 ± 0.6 mV, n = 18; p = 0.84) and input resistance (19.3 ± 1.1 M, n = 17 vs 20.6 ± 0.7 M,
n = 18; p = 0.31), consistent with a
previous report (Chagnac-Amital et al., 1990). However, the morphology
of these two populations of large layer 5 pyramidal neurons was
different (Chagnac-Amital et al., 1990; Tseng and Prince, 1993). RS
cells (n = 18) had a longer apical dendrite than IB
cells (n = 18; 1256 ± 118 vs 1194 ± 71 µm; p < 0.05) but a slightly smaller soma (SA:
2613 ± 401 vs 2945 ± 616 µm2; p < 0.05). The
distance from the soma at which the apical dendrites form their main
bifurcation was the same in RS cells and IB cells (0.58 ± 0.09, n = 17 vs 0.60 ± 0.09, n = 18;
p = 0.47; the length of the apical dendrite was
normalized as 1). The dendritic branch patterns of these cells and 16 P14 cells were quantified and compared by using the Sholl (1956)
analysis (Fig. 8D). We found that RS cells had
significantly fewer basal dendritic branches than IB cells
(p < 0.05), whereas those of IB and P14 cells
were the same (p = 0.68). RS and IB cells had
the same number of apical dendritic branches (p = 0.11), which was significantly more than that of P14 cells
(p < 0.05). These results indicate that the
postnatal differentiation from a single population of large layer 5 pyramidal neurons into RS and IB cells is likely dependent on the
maturation of both membrane and morphological properties.
We wanted to know whether intrinsic firing modes of layer 5 neurons affect the initiation of dendritic
Ca2+-dependent potentials. We first
examined the initiation of dendritic Ca2+-dependent potentials in RS and IB
neurons by using long step current injections as stimuli (Fig.
8E,F). We found that a low-intensity current
injection evoked tonic firing of Na+
action potentials in the soma and a train of fast, small
back-propagating action potentials in the dendrite of RS neurons.
Increasing current intensity eventually could evoke a cluster or burst
of two or more Na+ action potentials at
the onset of the response in the soma, followed by a large, slow
Ca2+-dependent potential in the dendrite
of these neurons. In contrast, a low-intensity current injection evoked
bursts of Na+ action potentials in the
soma and repetitive large, slow
Ca2+-dependent potentials in the dendrite
of IB neurons. Increasing current injection intensity eventually could
transform the later bursts into tonic firing of
Na+ action potentials in the soma,
followed by a train of fast, small back-propagating action
potentials in the dendrite of these neurons. We then examined the
initiation of dendritic Ca2+-dependent
potentials in pyramidal neurons by using synaptic stimulations as
stimuli (Fig. 8G-I). We found that, independent of
synaptic stimulation intensity, synaptic stimulation of deep layers
always evoked single Na+ action potentials
in the soma of P14 cells, followed by fast, large back-propagating
action potentials in the tuft dendrite. RS cells fired a single action
potential in the soma and a fast, small back-propagating action
potential in the dendrite in response to a weak stimulus. Increasing
stimulation intensity eventually could cause a burst of somatic action
potentials in these cells and a large, slow
Ca2+-dependent potential in the
dendrite. In contrast, IB cells fired a burst of action potentials in
the soma and a large, slow Ca2+-dependent
potential in the dendrite in response in response to a weak stimulus.
However, increasing stimulation intensity eventually could transfer the
burst into a single action potential in the soma and a fast, small
back-propagating action potential in the dendrite, attributable to the
fact that IB cells receive more GABAergic inputs and that these inputs
are activated only by strong stimuli (Chagnac-Amital et al., 1990;
Tseng and Prince, 1993). These results indicate that back-propagating
burst-evoked dendritic potentials signal somatic synaptic inputs
differently in RS cells and IB cells.
In summary, we show here that layer 5 pyramidal neurons have a
restricted action potential initiation zone in the apical dendrite, which can be activated by layer 1 synaptic inputs to initiate a mainly
Ca2+-dependent action potential in
vitro. These data combined with our previous reports complete the
description of the apical dendrites in terms of the regenerative nature
and location of the functionally different regions and their
interaction with each other (Larkum et al., 1999a,b, 2001; Zhu, 2000).
However, the question remains as to whether these forms of regenerative
potentials recorded in vitro can be induced by synaptic or
sensory inputs in the intact brain and whether their biophysical
properties are altered, because certain physiological conditions in the
intact brain can be quite different to in vitro ones. For
example, a substantial proportion of the apical dendritic tree of layer
5 pyramidal neurons is trimmed in the thin brain slices, and it is
likely that both excitatory and inhibitory circuits are impaired
in vitro. In addition, spontaneous synaptic activity is
prevalent in the intact brain (Zhu and Connors, 1999), and it is still
poorly understood how this spontaneous activity affects the integration
of distal synaptic inputs (Kamondi et al., 1998). Moreover,
neuromodulators are being released continuously in the intact brain,
and they are expected to modulate synaptic and dendritic properties to
a great extent (Chen and Lambert, 1997; Wu and Saggau, 1997; Zhu and
Heggelund, 2001). Therefore, we decided to make whole-cell recordings
at the soma and different locations along the apical dendrite of layer
5 pyramidal neurons in the anesthetized rat to study the initiation and
propagation of synaptic stimulation and whisker-evoked dendritic potentials.
Spontaneous activity-evoked dendritic regenerative potentials
in vivo
Whole-cell recordings were made from the soma and apical dendrite
of 53 layer 5 pyramidal neurons in anesthetized rats. The cell
morphology of all 53 pyramidal neurons was recovered so that the exact
recording sites from these neurons could be determined after the
reconstruction of the electrode-advancing pathway (Fig. 9A). As with in
vitro recordings (see above; Zhu, 2000; Berger et al., 2001), the
resting membrane potential became progressively more depolarized when
the recordings along the apical dendrite were made more and more distal
from the soma, whereas the input resistance remained relatively
constant along the apical dendrite (Fig. 9B).
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Figure 9.
Spontaneous synaptic input-evoked dendritic
regenerative potentials in the apical dendritic tuft. A,
The schematic drawing of the recording pipette indicates the location
of the dendritic recording (578 µm distal from the soma; dendritic
trunk). Note the biocytin staining of cell debris
(black) along the electrode penetration pathway (the
same in the following figures). The length of the apical dendrite was
1370 µm. B, Plots of resting membrane potential and
input resistance against distance from the soma of all layer 5 pyramidal neurons recorded in vivo. C,
Spontaneous activity evoked three distinct forms of regenerative
potentials in the layer 5 pyramidal neuron reconstructed in
A. They were fast potential (red), slow
potential (blue), and complex potential
(green). D, Histogram of dendritic
regenerative events with different duration. The resting membrane
potential at the dendritic trunk was 64 mV.
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Whole-cell in vivo recordings revealed numerous spontaneous
synaptic inputs in the soma and apical dendrites of layer 5 pyramidal neurons (Fig. 9C). When the spontaneous EPSPs were large
enough, they triggered regenerative potentials. In the apical dendrite three distinct forms of regenerative potentials were observed (Fig.
9C). The differences between these three potentials were seen best when the recordings were made from the corresponding dendritic action potential initiation zone determined in
vitro. One form of regenerative potentials had a fast rising phase
and a quick decaying phase (Fig. 9C, top trace),
which we refer to as fast potentials. The second form rose quickly but
decayed slowly (Fig. 9C, middle trace), and we
refer to these as slow potentials. The third form of regenerative
potentials appeared as a combination of a fast potential and a very
slow potential with one to seven peaks and dips (Fig. 9C,
bottom trace). We refer to these as complex potentials.
These three regenerative potentials also could be separated according
to their duration (Fig. 9D). Whereas fast potentials could
last up to 10 msec, slow potentials ranged from 12 to 18 msec in the
distal dendritic trunk and primary tuft branches. The duration of
complex potentials varied significantly, ranging from 18 to 40 msec.
This was attributable in part to the large variation in interval
between the fast and slow component, ranging from 3.4 to 13.7 msec, and
to the large difference in the number of peaks and dips they had. In
four distal dendritic trunk or primary tuft recordings, over 300 spontaneous regenerative events were collected for each recording, and
the relative occurrence of each form of regenerative potentials was
quantified. Fast potentials were the most frequently observed
regenerative events (69.4 ± 7.2%), followed by complex
potentials (28.8 ± 7.5%). Slow potentials occurred at a very low
incidence of 1.8 ± 0.7%.
Whisker-evoked fast and complex potentials in vivo
Depending on where the recordings were made, the amplitude and
duration of fast potentials varied. They were smaller in amplitude and
longer in duration when recorded from the tuft branches (Fig. 10A,B) but larger in
amplitude and shorter in duration when recorded from the proximal
dendritic trunk (Fig. 10C,D). There were linear correlations
between the average amplitude (r = 0.90;
p < 0.0001; n = 53; ANOVA) or average
duration (r = 0.91; p < 0.0001;
n = 53; ANOVA) of fast potentials and the distance from
recording site to the soma (Fig. 10E). These results
suggest that fast potentials originate from back-propagating
Na+ action potentials initiated in the
axonal action potential initiation zone (Larkum et al., 2001). In
addition to spontaneous inputs, a brief deflection of single whiskers
frequently induced a fast potential (Fig. 10B,D).
Because the ascending sensory inputs arrive primarily at layer 4 in
anesthetized animals (Cauller and Kulics, 1988), such input would be
expected to generated Na+ potentials at
the soma, which is consistent with the idea that fast potentials result
from back-propagating Na+ potentials. The
small sample of distal dendritic recordings, however, does not allow us
to validate whether the variability in amplitude of back-propagating
potentials, reported by recent in vitro studies (Golding et
al., 2001; Larkum et al., 2001), exists in the intact brain.
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Figure 10.
Spontaneous synaptic input and whisker-evoked
fast and complex potentials in the apical dendritic tuft.
A, The schematic drawing of the recording pipette
indicates the location of the dendritic recording (1042 µm distal
from the soma; tertiary tuft). The length of the apical dendrite was
1179 µm. B, Spontaneous input and whisker-evoked fast
regenerative potentials in the layer 5 pyramidal neuron reconstructed
in A. C, The schematic drawing of the
recording pipette indicates the location of the dendritic recording
(612 µm distal from the soma; dendritic trunk). The length of the
apical dendrite was 1257 µm. D, Spontaneous input and
whisker-evoked fast regenerative potentials in the layer 5 pyramidal
neuron reconstructed in C. E, Plots of
fast potential amplitude and duration against distance from the soma of
all layer 5 pyramidal neurons recorded in vivo.
F, Spontaneous input and whisker-evoked complex
potentials in the layer 5 pyramidal neuron reconstructed in
C. G, Plot of complex potential amplitude
against distance from the soma of all layer 5 pyramidal neurons
recorded in vivo. The resting membrane potentials at the
tertiary tuft and dendritic trunk were 65 and 70 mV,
respectively.
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Sometimes a brief defection of whiskers induced a complex potential
(Fig. 10F). This result, as well as the waveform of
the potentials, suggests that complex potentials may result from bursts of back-propagating Na+ action potentials
and/or the interaction of single back-propagating Na+ action potentials with synaptic inputs
arriving at the dendritic action potential initiation zone (Fig. 8)
(Larkum et al., 1999a,b). The maximum amplitude of the complex
potentials decreased as a function of distance from the soma (Fig.
10G). At the distal dendritic trunk and low-order tuft
branches their peak amplitude, dependent primarily on
Ca2+ conductance (Larkum et al., 2001),
remained relatively constant. This is consistent with our in
vitro observation that a low-threshold zone with a high density of
Ca2+ channels is present around the
bifurcation region of the apical dendrite of layer 5 pyramidal neurons.
The lone tertiary tuft recording gave a smaller complex potential,
supporting our view that active conductances diminish in the terminal
dendrite. The result is also consistent with the in vivo
imaging result of reduced Ca2+ influx in
the distal dendritic tips during the activation of dendritic
regenerative potentials (Helmchen et al., 1999).
Layer 1 stimulation-evoked slow potentials in vivo
Spontaneous slow potentials occurred rarely in anesthetized rats.
Moreover, whisker deflections never induced any slow potential in our
dendritic recordings. Because layer 1 inputs arrive at the distal tuft
and they are suppressed in large part in anesthetized animals (Cauller
and Kulics, 1988, 1991), we speculated that these inputs have a large
influence on the initiation of slow potentials in the distal dendrite.
We thus made recordings from the apical dendrite and stimulated the
cortical surface directly to activate layer 1 fibers (Fig.
11A) (cf. Chang,
1951a). Cortical surface stimulation induced an EPSP, which could
trigger a slow potential just like those spontaneously occurred ones
(Fig. 11B). The evoked EPSP had a smooth, fast rising
phase and exhibited little jittering in latency, suggesting a putative
monosynaptic event. This result is consistent with the early suggestion
that the response was attributable to the direct activation of the
apical dendrite of layer 5 pyramidal neurons by layer 1 inputs (Chang,
1952). Interestingly, before reaching threshold, the EPSP showed a
step-wise increase in amplitude in response to the increase of
stimulating intensity, suggesting recruitment of presumably a small
number of presynaptic fibers. On average, the activation of 4.7 ± 1.2 (n = 3) steps was required to trigger a slow
potential in the dendrite of layer 5 pyramidal neurons in the intact
brain.
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Figure 11.
Spontaneous synaptic input and layer 1 stimulation-evoked slow potentials in the apical dendritic tuft.
A, The schematic drawing of the recording pipette
indicates the location of the dendritic recording (769 µm distal from
the soma; primary tuft). The length of the apical dendrite was 1362 µm. B, Spontaneous input and layer 1 stimulation-evoked slow regenerative potentials in the layer 5 pyramidal neuron reconstructed in A. Shown is the plot
of peak voltage response as a function of layer 1 stimulation
intensity. C, The schematic drawing of the recording
pipette indicates a somatic recording. The length of the apical
dendrite was 1166 µm. D, Spontaneous input and layer 1 stimulation evoked a large, fast potential and burst of action
potentials in the soma of the layer 5 pyramidal neuron reconstructed in
C. The inset shows a whisker-evoked EPSP.
Note the slow rise of the EPSP before it triggered a burst of sodium
action potentials (sodium action potentials are truncated). Shown is
the plot of peak voltage response as a function of layer 1 stimulation
intensity. E, Paired layer 1 stimuli revealed the
refractory period of the slow dendritic potential in the dendrite
recorded from the layer 5 pyramidal neurons reconstructed in
A. The data points in the plot were
obtained from three different neurons. F, Paired layer 1 stimuli revealed the refractory period of the large fast potential
recorded from the soma of the layer 5 pyramidal neurons reconstructed
in C. The data points in the plot were
obtained from four different neurons. The resting membrane potentials
at the soma and dendrite were 71 and 65 mV, respectively.
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To test how slow potentials affect the somatic firing, we used cortical
surface stimulation while making recordings from the soma of layer 5 pyramidal neurons (Fig. 11C). Low-strength cortical surface
stimulation induced an EPSP in the soma (Fig. 11D).
When the stimulation reached the threshold, it triggered a large, fast rising potential and typically a burst of
Na+ action potentials. The average number
of Na+ action potentials in the bursts was
1.8 ± 0.2 (n = 12). Occasionally, similar large
and fast potentials occurred as spontaneous events (Fig.
11D). The quick rising phase of these potentials
distinguished them from those spontaneous or whisker-evoked bursts that
ride on a slow EPSP (Fig. 11D, inset).
Like slow potentials recorded in the dendrite, cortical surface
stimulation also induced a step-wise increase in amplitude of the
response, with 4.3 ± 0.7 (n = 7) activation steps
required to trigger a large, fast depolarization and burst firing. This
threshold is the same as the one for inducing slow potentials in the
dendrite (p > 0.5), indicating that slow dendritic potentials originate from the activation of layer 1 fibers in
the cortex and that they evoke a large depolarization and a burst of
Na+ action potentials at the soma of layer
5 pyramidal neurons. These results also predict that slow dendritic
potentials and large, fast rising somatic depolarization are more
frequent events in awake animals, because layer 1 inputs are enhanced
dramatically in that behavioral state (Cauller and Kulics, 1988, 1991).
Although the regenerative potentials initiated in the distal dendrite
always actively propagate in the distal trunk in vitro,
recordings also show that they can either propagate actively or spread
passively to the soma along the proximal dendrite (Figs. 3B,
4) (see also Larkum et al., 2001). However, the fast rising phase of
large somatic potentials recorded in vivo suggests that slow
potentials propagate actively all the way along the apical dendrite to
the soma in the intact brain.
The refractory period of cortical surface stimulation-evoked potentials
was examined by using paired stimuli (Fig.
11E,F). Paired stimuli with varying intervals
showed that the second stimulus often failed to evoke a regenerative
potential if the interval was too short. Varying the interval of two
stimuli and stimulation intensity of the second stimulus revealed a
relative refractory period of ~250 msec for the slow potentials in
the dendrite (n = 3) and large, fast potentials in the
soma (n = 4). This refractory period is the same as
that of the regenerative potentials initiated in the distal dendrite
in vitro (Fig. 2F). The results supports the view that the slow potentials in the dendrite and large, fast potentials in the soma are attributable to the activation of layer 1 inputs and distal dendritic action potential initiation zone.
There was a notable difference between synaptically evoked responses in
the dendrite in vivo and in vitro (Fig.
12). Although the threshold for
inducing synaptic responses was the same in vivo and
in vitro (5.3 ± 0.3 V, n = 6 vs
7.8 ± 0.9 V, n = 16; p = 0.10),
the minimal EPSP evoked by the threshold stimulus was significantly
larger in vivo than in vitro (4.56 ± 0.76 mV, n = 6 vs 1.43 ± 0.26 mV, n = 16; p < 0.0005), with the amplitude ranging from
2.11 to 7.17 mV in vivo and from 0.56 to 4.31 mV in vitro. Because single presynaptic axons can make multiple
synapses on the different dendritic branches of single postsynaptic
pyramidal neurons (Lisman and Harris, 1993), one possible explanation
for the result is that some of the synapses made by single layer 1 fibers on the tuft branches of layer 5 pyramidal neurons are removed when the apical dendrite tree is trimmed during slicing. Consistent with the idea, we found that the threshold for activation of dendritic regenerative potentials was significantly lower in vivo than
in vitro (11.5 ± 1.8 V, n = 6 vs
31.3 ± 1.5 V, n = 16; p < 0.0005). Further study is required to confirm this idea and/or to
determine other mechanisms that may be responsible for the
difference.
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Figure 12.
Threshold and amplitude of synaptic responses in
the apical dendrite in vitro and in vivo.
Left, Amplitude of minimal evoked EPSP recorded in the
apical dendrite in vitro and in vivo.
Right, Threshold for evoked dendritic EPSPs and
Ca2+-dependent regenerative potentials in
vitro and in vivo. *p < 0.05 (Student's t test).
|
|
| |
DISCUSSION |
Our in vitro experiments demonstrate that the apical
dendrite of adult (> P42) thick-tufted pyramidal neurons in cortical layer 5 has a low-threshold region for the initiation of mostly Ca2+-dependent regenerative potentials.
This zone is situated in the apical dendrite ~550-900 µm from the
soma, including typically the distal dendritic trunk and the primary
and secondary tufts. In in vitro conditions, dendritic
regenerative potentials can be restricted locally to the distal
dendritic arbor without inducing somatic firing, but more frequently
they propagate actively for some distance, then either continuously
travel actively or spread passively along the proximal dendrite toward
the soma, where they induce a burst of two to four action potentials.
Our in vivo experiments confirm that layer 1 inputs can
activate the dendritic action potential initiation zone and evoke
regenerative potentials propagating actively toward the soma, where
they induce one to three Na+ action
potentials. In addition, back-propagating
Na+ action potentials by themselves or by
interacting with the dendritic action potential initiation zone evoke
fast and complex potentials in dendrite in vivo. Sensory
inputs from whiskers trigger either a fast potential or a complex
potential when they reach threshold.
Multiple forms of dendritic potentials
Previous studies have shown that active conductances, such as
Na+ and Ca2+
conductances, are present in the apical dendrite of pyramidal neurons
(Huguenard et al., 1989; Stuart and Sakmann, 1994; Yuste et al., 1994;
Magee and Johnston, 1995b; Markram et al., 1995; Kavalali et al.,
1997). The initial phase of dendritic potentials is predominantly
Na+-dependent because it is blocked by TTX
(Larkum et al., 2001). The slower phase of regenerative potentials is
mediated primarily by Ca2+ conductances
(Zhu, 2000; Larkum et al., 2001). As with younger neurons (Wei et al.,
2001), the distribution of high-density active conductances extends to
the primary and secondary tuft branches, because regenerative
potentials can be induced in these branches with low threshold.
Interestingly, the density of active conductances in the very distal
dendrites (i.e., the tertiary and quaternary tufts) appears reduced
when compared with the bifurcation region, suggesting a more passive
membrane for the dendritic terminals. This result explains the reduced
Ca2+ influx observed in the distal
dendritic tips during the activation of dendritic regenerative
potentials in vivo (Helmchen et al., 1999).
Although dendritically initiated regenerative potentials often
forward-propagate and depolarize the axonal action potential initiation
zone reliably to give rise to a burst of action potentials in
vitro, there are conditions under which they can be restricted locally without inducing somatic firing (Larkum et al., 2001). However, in the intact brain, slow dendritic potentials propagate reliably to the soma because suprathreshold layer 1 inputs evoke all-or-none potentials in both distal dendrite and soma with the same
threshold. More interestingly, judged by the fast rising phase of the
layer 1 input-evoked large depolarization in the soma, slow dendritic
potentials appear to propagate actively all the way to the soma
in vivo, whereas only approximately one-half of neurons do
so in vitro (Larkum et al., 2001). This result suggests that
the in vivo condition is more favorable for active
propagation of dendritic potentials (cf. Rhodes and Llinas, 2001). This
may be attributable to the intact circuit in vivo, which
generates stronger, more synchronized spontaneous and evoked excitatory and inhibitory inputs in postsynaptic neurons than in vitro.
Although these synaptic inputs would be expected to decrease the
amplitude of regenerative potentials by increasing membrane
conductance, they also would be expected to facilitate the activation
of regenerative currents by shortening the membrane time constant. In
addition, a higher temperature (37°C in vivo vs 35°C
in vitro) also may contribute somewhat to the reliable
propagation, because calcium channel kinetics are highly sensitive to
the temperature (Q10  3; Coulter et al., 1989;
McAllister-Williams and Kelly, 1995). Indeed, changing the temperature
in the recording chamber from 35 to 30°C is enough to result in a
large increase in membrane input resistance and a transformation of
forward-propagating dendritic potentials into locally restricted ones
without inducing somatic firing in vitro [our unpublished
data; see also Wei et al. (2001) for locally restricted potentials
recorded at room temperature], consistent with these ideas. It is
worthwhile noting that dendritic regenerative potentials recorded in
the immature tuft dendrites in vitro often are restricted
locally and tend not to induce somatic firing (Schiller et al., 1997;
Zhu, 2000), attributable in part to fewer active channels available in
the initiation zone at this developmental stage (Zhu, 2000). However,
it remains to be determined whether the regenerative potentials
initiated in young tufts can cause a depolarization large enough to
induce somatic Na+ action potentials in
the intact brain.
Besides locally initiated slow potentials, active conductances in the
distal dendrite support single back-propagating fast potentials, which
may be mediated primarily by Na+ channels
(Stuart and Sakmann, 1994; Larkum et al., 2001). The complex potentials
recorded in this study are likely to be dependent on the activation of
both Na+ and
Ca2+ channels (Larkum et al., 1999a,b,
2001). Because a large amount of Ca2+
influx is detected around the bifurcation range of the apical dendrite
when burst firing is induced at the soma of layer 5 pyramidal neurons
by depolarizing current injection or spontaneous activity (Helmchen et
al., 1999), some of the complex potentials probably result from
back-propagating bursts of Na+ action
potentials (Fig. 8) (Larkum et al., 1999b). However, back-propagating bursts are unlikely to be responsible for all complex potentials because some complex potentials recorded in vivo can have an
interval between the fast and slow component >13 msec, and it is
possible for the back-propagating bursts of
Na+ of action potentials to initiate
complex potentials only when their intraburst frequency surpasses a
critical frequency (i.e., >80 Hz; Larkum et al., 1999b). Thus some of
the complex potentials are more likely to have been produced by the
interaction of single back-propagating Na+
of action potentials and distal subthreshold synaptic inputs (Larkum et
al., 1999a). Clearly, more in vivo experiments are needed to
determine the origin of complex potentials.
Functional significance
The properties of dendritically initiated regenerative potentials
are very different from axonal ones. Therefore, the two initiation
sites of pyramidal cells most likely have different functions in
neuronal signaling. Dendritic regenerative potentials have a 10- to
20-fold longer duration than Na+-dependent
axonal action potentials and much longer (~20-fold) absolute and
relative refractory periods. This long refractory period would allow
suprathreshold repetitive excitatory signals arriving in the
tuft dendrites to be "transmitted" to the soma only at a relatively
low frequency.
Alternatively, the apical dendrites may function as a "mode switch"
for different output action potential patterns. The main inputs to
dendritic tufts are from the higher-order cortical areas (Zeki and
Shipp, 1988; Felleman and Van Essen, 1991; Johnson and Burkhalter,
1997; Cauller et al., 1998), cholinergic and monoaminergic nuclei (De
Lima and Singer, 1986; Lysakowski et al., 1986), and secondary
ascending sensory system (Herkenham, 1979; Casagrande, 1994; Jones,
1998). These inputs can generate a prolonged depolarization in their
target neurons (Benardo, 1993; Shao and Burkhalter, 1996). The
long-lasting depolarizations (Fig. 1B) (Zhu, 2000),
together with the intrinsic (Silva et al., 1991; Amitai, 1994) and
synaptic (Reyes and Sakmann, 1999) properties of adult layer 5 pyramidal neurons, may promote bursts at alpha rhythm for a short
period. Because the alpha rhythm may be related to mechanisms of
attention (Ray and Cole, 1985; Vanni et al., 1997), one speculation is
that distal synaptic inputs are used to form an
"attentional/select" window (Squire and Zola-Morgan, 1991;
Olshausen et al., 1993). Namely, when layer 1 attentional signals
"switch" a group of layer 5 pyramidal neurons into the burst firing
mode, they secure that salient and/or ambiguous sensory information
from layer 4 input is amplified in these cells and relayed to their
target cells (Lisman, 1997; Williams and Stuart, 1999; Zhu, 2000). This
notion is supported by the finding that layer 1 activity is suppressed in sleeping animals but dramatically enhanced in alert animals (Cauller
and Kulics, 1988). Thus the dendritic regenerative potential initiation
zone may play a key role in attention-related information processing.
Back-propagating action potential-evoked fast and complex potentials
may be important for transferring somatic information back to the
distal dendrite. In the young animals single
Na+ action potentials back-propagate to
the distal dendrite without much reduction in their amplitude (Stuart
and Sakmann, 1994). These large back-propagating signals appear to be
critical for the induction of synaptic plasticity, such as the
long-term potentiation between layer 5 pyramidal neurons (Markram et
al., 1997). However, single back-propagating
Na+ action potentials can produce only a
very small depolarization (Fig. 10) and cause little
Ca2+ influx in the adult tuft dendrites
(Helmchen et al., 1999), and they appear not to be effective in
inducing long-term potentiation in adult pyramidal neurons (Thomas et
al., 1998; Pike et al., 1999). Thus the maturation of the dendritic
action potential initiation zone (Zhu, 2000) and back-propagating
burst-evoked complex potentials may be crucial for the efficient
induction of long-term synaptic plasticity in the adult distal dendrite
of layer 5 pyramidal neurons by back-propagating signals.
| |
FOOTNOTES |
Received Jan. 23, 2002; revised May 28, 2002; accepted May 29, 2002.
This work was supported in part by the Alzheimer's Association, the
Fraxa Medical Research Foundation, and the Max Planck Society. J.J.Z.
is a Naples Investigator of the National Alliance for Research on
Schizophrenia and Depression Foundation. We thank Professor Bert
Sakmann for his support and discussions; Drs. Hsiang-Tung Chang, Alon
Krongreen, Troy Margrie, and Arnd Roth for their helpful comments; and
Drs. Katharina Kaiser and Yi Qin for help in some experiments and
histological processing.
Correspondence should be addressed to Dr. J. Julius Zhu, Department of
Pharmacology, University of Virginia School of Medicine, 1300 Jefferson
Park Avenue, Charlottesville, VA 22908. E-mail: jjzhu{at}virginia.edu.
| |
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M. E. Larkum, W. Senn, and H.-R. Luscher
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Y. Zhu, R. L. Stornetta, and J. J. Zhu
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I. D. Manns, B. Sakmann, and M. Brecht
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T. Nevian and B. Sakmann
Single Spine Ca2+ Signals Evoked by Coincident EPSPs and Backpropagating Action Potentials in Spiny Stellate Cells of Layer 4 in the Juvenile Rat Somatosensory Barrel Cortex
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Y. Zhu and J. J. Zhu
Rapid Arrival and Integration of Ascending Sensory Information in Layer 1 Nonpyramidal Neurons and Tuft Dendrites of Layer 5 Pyramidal Neurons of the Neocortex
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C. E. Young and C. R. Yang
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Y. Gonchar and A. Burkhalter
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T. Berger, W. Senn, and H.-R. Luscher
Hyperpolarization-Activated Current Ih Disconnects Somatic and Dendritic Spike Initiation Zones in Layer V Pyramidal Neurons
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J. Waters, M. Larkum, B. Sakmann, and F. Helmchen
Supralinear Ca2+ Influx into Dendritic Tufts of Layer 2/3 Neocortical Pyramidal Neurons In Vitro and In Vivo
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J. H Goldberg, R. Yuste, and G. Tamas
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A. T. Schaefer, M. E. Larkum, B. Sakmann, and A. Roth
Coincidence Detection in Pyramidal Neurons Is Tuned by Their Dendritic Branching Pattern
J Neurophysiol,
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N. Hardingham, S. Glazewski, P. Pakhotin, K. Mizuno, P. F. Chapman, K. P. Giese, and K. Fox
Neocortical Long-Term Potentiation and Experience-Dependent Synaptic Plasticity Require {alpha}-Calcium/Calmodulin-Dependent Protein Kinase II Autophosphorylation
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M. E Larkum, S. Watanabe, T. Nakamura, N. Lasser-Ross, and W. N Ross
Synaptically activated Ca2+ waves in layer 2/3 and layer 5 rat neocortical pyramidal neurons
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T. Berger and H.-R. Luscher
Timing and Precision of Spike Initiation in Layer V Pyramidal Cells of the Rat Somatosensory Cortex
Cereb Cortex,
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Z. Chu, M. Galarreta, and S. Hestrin
Synaptic Interactions of Late-Spiking Neocortical Neurons in Layer 1
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M.-C. Perreault, Y. Qin, P. Heggelund, and J J. Zhu
Postnatal development of GABAergic signalling in the rat lateral geniculate nucleus: presynaptic dendritic mechanisms
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
