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The Journal of Neuroscience, July 15, 2000, 20(14):5208-5216
Long-Term Potentiation of Intrinsic Excitability at the Mossy
Fiber-Granule Cell Synapse of Rat Cerebellum
S.
Armano1,
P.
Rossi1,
V.
Taglietti1, and
E.
D'Angelo1, 2
1 Department of Cellular/Molecular Physiology and
Pharmacology, and INFM (Pavia Unit), I-27100 Pavia, Italy, and
2 Department of Functional and Evolutive Biology, Parco
Area delle Scienze 11A, I-43100 Parma, Italy
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ABSTRACT |
Synaptic activity can induce persistent modifications in the way a
neuron reacts to subsequent inputs by changing either synaptic efficacy
or intrinsic excitability. After high-frequency synaptic stimulation,
long-term potentiation (LTP) of synaptic efficacy is commonly observed
at hippocampal synapses (Bliss and Collingridge, 1993 ), and
potentiation of intrinsic excitability has recently been reported in
cerebellar deep nuclear neurons (Aizenmann and Linden, 2000).
However, the potential coexistence of these two aspects of plasticity
remained unclear. In this paper we have investigated the effect of
high-frequency stimulation on synaptic transmission and intrinsic
excitability at the mossy fiber-granule cell relay of the cerebellum.
High-frequency stimulation, in addition to increasing synaptic
conductance (D'Angelo et al., 1999), increased granule cell input
resistance and decreased spike threshold. These changes depended on
postsynaptic depolarization and NMDA receptor activation and were
prevented by inhibitory synaptic activity. Potentiation of intrinsic
excitability was induced by relatively weaker inputs than potentiation
of synaptic efficacy, whereas with stronger inputs the two aspect of
potentiation combined to enhance EPSPs and spike generation.
Potentiation of intrinsic excitability may extend the computational
capability of the cerebellar mossy fiber-granule cell relay.
Key words:
synaptic plasticity; LTP; NMDA receptors; cerebellum; granule cells; intrinsic excitability; E-S potentiation
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INTRODUCTION |
In addition to causing transient
modifications in neuronal potential, synaptic activity can induce
changes in the way a neuron responds to subsequent inputs. This
property, which is called synaptic plasticity, can entail persistent
changes in both synaptic efficacy and intrinsic neuronal excitability.
Although these two aspects of plasticity may concur to improve neuron
and network computation (Fregnac, 1998), their potential coexistence
remained unclear.
A well known model for synaptic plasticity is long-term potentiation
(LTP), which is typically induced by high-frequency activation of
NMDA receptors at glutamatergic synapses (Bliss and
Collingridge, 1993; Bear and Malenka, 1994). Synaptic efficacy is
enhanced during LTP. However, in hippocampal pyramidal cells the
probability of action potential activation increases more than expected
from potentiation of synaptic efficacy (E-S potentiation) (Bliss and Lömo, 1973; Andersen et al., 1980), suggesting that additional factors are involved. E-S potentiation was usually shown to depend on
depression of synaptic inhibition (Abraham et al., 1987; Chavez-Noriega et al., 1990; Breakwell et al., 1996), although in some cases an
intrinsic excitability change was suggested (Pugliese et al., 1994; Daoudal et al., 1999).
Activity-dependent changes in intrinsic excitability are common in the
developing brain (Spitzer, 1991); their mechanisms have been
investigated in cell culture (Turrigiano et al., 1994; Desai et al.,
1999), and their computational implications have been predicted by
using theoretical models (Stemmler and Koch, 1999). Recently, an NMDA
receptor-dependent potentiation in intrinsic excitability has been
observed in cerebellar deep nuclear neurons after high-frequency
tetanic stimulation similar to that used to induce LTP, although in the
absence of any synaptic efficacy changes (Aizenman and Linden,
2000).
We have investigated whether changes in intrinsic excitability could be
induced by high-frequency stimulation of the mossy fiber-granule cell
synapse of the cerebellum, at which NMDA receptor-dependent LTP has
recently been demonstrated (D'Angelo et al., 1999). After pharmacological blockage of inhibitory synapses, high-frequency stimulation induced an NMDA receptor-dependent potentiation of intrinsic excitability. This depended on a rise in input resistance and
a decrease in spike threshold, which enhanced EPSPs and spike firing.
Together with potentiation of synaptic conductance, potentiation of
intrinsic excitability may play an important role in regulating granule
cell synaptic excitation and cerebellar network computation.
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MATERIALS AND METHODS |
Acute 250-µm-thick cerebellar slices were obtained from 19- to-22-d-old Wistar rats as reported previously (D'Angelo et al., 1999). The rats were anesthetized with halothane (Aldrich, Milwaukee, WI) before being killed by decapitation. Slices were cut in the sagittal plane from the cerebellar vermis in cold Krebs' solution and
maintained at room temperature before being transferred to a 1.5 ml
recording chamber mounted on the stage of an upright microscope (Zeiss
Standard-16). The preparations were superfused with Krebs' solution
and maintained at 30°C with a feedback Peltier device (HCC-100A;
Dagan Corporation, Minneapolis MN).
The Krebs' solution contained (in mM): NaCl 120, KCl 2, MgSO4 1.2, NaHCO3 26, KH2PO4 1.2, CaCl2 2, glucose 11, and was equilibrated with
95% O2 and 5% CO2, pH
7.4. The control and test solutions were applied locally through a
multi-barrel pipette. Perfusion of the control solution was commenced
before seal formation and was maintained until switching to the test
solutions. Unless stated otherwise, the perfused solutions contained
the GABA-A receptor blocker 10 µM bicuculline. Nystatin
and bicuculline were obtained from Sigma (St. Louis, MO), and the
glutamate receptor antagonists D-2-amino-5-phosphonovaleric
acid (APV), 7-chlorokinurenic acid (7-Cl-kyn), and
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were obtained from Tocris
Cookson (Bristol, UK).
Whole-cell patch-clamp recordings were performed in granule cells using
the perforated-patch technique, which prevents cytoplasmic washout
(Horn and Marty, 1988; Edwards et al., 1989). The pipette solution
contained (in mM):
K2SO4 80, NaCl 10, glucose
15, HEPES 5 (pH adjusted to 7.2 with KOH), and nystatin 100 µg/ml.
Membrane potential was measured relative to an Ag-AgCl reference
electrode (Clark Instruments, Pangbourne, UK) and was not corrected for the Donnan potential developing across the patch ( 5 mV inside the
cell). Electrical activity was recorded with an Axopatch 200-B amplifier, sampled with a Digidata 1200B interface (500 µsec/point), and analyzed off-line with P-Clamp software (Axon Instruments). The
mossy fibers were stimulated with a bipolar tungsten electrode via a
stimulus isolation unit.
In a typical experiment, mossy fibers were activated at a frequency of
0.1 Hz, and step current pulses were applied every 5 min from the
membrane potential of 80 mV. High-frequency pulses were delivered 10 min after establishing the whole-cell recording configuration
(time = 0) either as a theta-burst stimulation (TBS; four 100 msec, 100 Hz bursts of impulses repeated every 250 msec) or continuous
stimulation (CS; one 1000 msec, 100 Hz burst of impulses) from
potentials between 60 and 90 mV.
Membrane potential during step current injection was estimated as the
average value between 500 and 800 msec. Membrane potential during TBS
was estimated as the mean of average values measured in the central 70 msec of each burst (tracings were filtered at 100 Hz). The action
potentials consisted of two components, the prepotential and the
upstroke (D'Angelo et al., 1998). The threshold of spike prepotential
(Th1) was measured at the flexus in
the interspike trajectory, whereas that of the upstroke
(Th2) was measured at the sharp
transition from prepotential to upstroke (see Fig. 5,
inset). Th1 coincided with
the minimum depolarization necessary to activate an action potential,
whereas Th2 approached the
depolarization reached by those prepotentials that did not initiate the
ballistic phase of the action potential (examples are shown in Figs.
3B, 4A,B, and
7A). In some cases, threshold identification was aided by
taking the first time derivative of the signal (data not shown). Data
are reported as mean ± SD, and statistical comparisons were
performed using Student's t test.
Just after obtaining the cell-attached configuration, electrode
capacitance was carefully cancelled to allow for electronic compensation of pipette charging during subsequent current-clamp recordings (D'Angelo et al., 1995). The cerebellar granule cell is
electrotonically compact and can be treated as a simple RC system, in which relevant parameters can be extracted by analyzing passive current relaxation induced by step voltage changes (D'Angelo et al., 1995, 1999; Silver et al., 1996). Monoexponential fitting to
current transients elicited by 10 mV hyperpolarizing voltage steps from
the holding potential of 80 mV yielded the voltage-clamp time
constant,  VC. The input capacitance
(Cin) was measured from the capacitive
charge (the area underlying current transients), and series resistance
(Rs) was calculated as
Rs = VC/Cin. Input resistance Rin was computed from the
steady current flowing after termination of the transient. When the
patch perforation had stabilized, typical granule cell values were
obtained [Cin = 3.1 ± 0.7 pF, Rin = 2.3 ± 0.5 G , and
Rs = 34.3 ± 17.2 M
(n = 18 for all measurements)].
Current-clamp recordings were performed in the "fast" operating
mode to optimize the reaction rate of the amplifier (D'Angelo et al.,
1998; Magistretti et al., 1998). The effect of
Rs in current-clamp recordings is
inversely proportional to Rin. Because
Rs was approximately two orders of
magnitude smaller than Rin, the effect
of Rs on voltage recordings was
negligible (~1%). For this reason, (1) perforated-patch recordings
were at no disadvantage to ruptured-patch recordings despite
Rs being nearly 50% higher; (2)
bridge balancing was unnecessary, and (3) recording stability was
ensured despite changes in Rs that
might occur during prolonged recordings. Recording stability was
attested by Rin measurements, as shown
in Figure 4.
Although perforated-patch recordings prevent cytoplasmic constituents
from being washed out, EPSP size and spike threshold showed a slow
time-dependent decrease (see Figs. 2C, 3C,
4C). This may reflect long-term modifications induced by
spike discharge (Pockett et al., 1990; Christofi et al., 1993;
Aizenmann and Linden, 2000) generated by step current pulses
used to monitor granule cell intrinsic excitability.
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RESULTS |
The effect of high-frequency mossy fiber stimulation on synaptic
efficacy and intrinsic granule cell excitability was investigated in
rat cerebellar slices at P19-P22, when granule cells show mature synaptic and excitable properties (D'Angelo et al., 1998), using whole-cell perforated-patch recordings (Horn and Marty, 1988).
Preliminary observations
Granule cells are excited by glutamatergic mossy fiber synapses
and inhibited by GABAergic Golgi cell synapses (Fig.
1A). EPSPs recorded
with 10 µM bicuculline in the bath to block
GABA-A receptors (Fig. 1B) measured between 8 and 22 mV in different experiments (compare Fig.
2). Considering that cerebellar granule cells receive four mossy fiber inputs on average (Eccles et al., 1967),
each causing an 8-12 mV depolarization (D'Angelo et al., 1995; Silver
et al., 1996), one to three mossy fiber synapses should have been
activated. Golgi cells can be activated directly by mossy fibers in the
glomeruli, as well as by granule cell axons, the parallel fibers
(Eccles et al., 1967). Mossy fiber stimulation in bicuculline-free
solution (i.e., with unblocked GABA-A receptors) caused strong granule
cell inhibition, curtailing EPSPs and preventing spike generation (cf.
tracings obtained before and after bicuculline application in Fig.
1B). Because parallel fibers are severed in sagittal
slices, Golgi cells should be preferentially activated through their
mossy fiber input rather than through the granule cell-parallel fiber
recurrent loop. Consistently, inhibition arose quickly (3-5 msec),
whereas longer delays would be expected for feedback inhibition (Vos et
al., 1999). IPSPs were evident at potentials positive to 64.2 ± 3.3 mV (n = 5) (Fig. 1C), above the chloride
equilibrium potential (66 mV) (see Materials and Methods) and the
granule cell resting potential (63.6 ± 8.9 mV; n = 10). Because GABAergic responses have a
depolarizing action below the chloride equilibrium potential, the
marked EPSP reduction observed in this membrane potential range
indicates that GABA receptors act through a shunting mechanism to
decrease granule cell input resistance. GABA-A receptors may also
operate through a tonic inhibition mechanism (Brickley et al., 1996),
because granule cell input resistance was 28% lower before bicuculline perfusion than after it (1.8 ± 0.7 G vs 2.5 ± 1.7 G;
n = 7).
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Figure 1.
Synaptic excitation and inhibition of
cerebellar granule cells. A, Schematic drawing of the
cerebellar network. GrC, Granule cell;
GoC, Golgi cell; PC, Purkinje cell;
mf, mossy fiber; pf, parallel fiber.
B, Granule cell synaptic responses elicited from two
different membrane potentials before and after 10 µM
bicuculline application. Bicuculline enhanced EPSPs and spike
generation. C, Granule cell synaptic responses elicited
from different membrane potentials in bicuculline-free solution. The
hyperpolarizing component of the response was present only above the
Cl equilibrium potential (66 mV). Amplitudes of
the depolarizing ( ) and hyperpolarizing ( ) components of the
response are plotted to the right
(symbols over tracings indicate where measurements were
taken).
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Figure 2.
LTP of excitatory transmission.
A1, A2, Effect of TBS
delivered from 70 mV in a solution containing 10 µM bicuculline. Control EPSPs activated from 80 mV
measured 9.1 ± 3.2 mV in A1 and 21.2 ± 4.3 mV in A2. LTP was manifest as an EPSP
increase, which was larger in A2 than
A1. In A2, EPSP growth
led to spike generation 7 min after TBS. B1 and
B2, Membrane depolarization during TBS
corresponding to recordings in A1,
A2. Note stronger depolarization and spike
generation in B2 than
B1. C, Average EPSP
potentiation in five cells as in A1 () and in
five cells as in A2 (; the point series is
interrupted because of spike generation). Results are compared with
control EPSP recordings in which no TBS was applied ( ;
n = 5). D, Potentiation of the
probability of firing during LTP in cells showing spikes during the
control period (n = 8). In this and the
following figures, an arrowhead ( ) and a
vertical dotted line indicate TBS. Data points are
reported as mean ± SD, and time is relative to beginning of
recordings.
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Mossy fibers convey complex patterns of high-frequency spike bursts
during movement (Kase et al., 1980) and can entrain the granular layer
to discharge at theta frequency (Pellerin and Lamarre, 1997; Hartmann
and Bower, 1998). In preliminary experiments we observed that
LTP was similar when it was induced by high-frequency stimulation
organized either in repeated bursts (TBS) or in a single continuous
burst (CS) (Table 1). TBS was thus
preferred because it allowed a closer comparison with previous
voltage-clamp experiments (D'Angelo et al., 1999).
EPSP potentiation
In an initial set of experiments, LTP was investigated during
GABA-A receptor blockage by 10 µM bicuculline. LTP
recordings were grouped depending on membrane depolarization efficiency
during TBS, which in turn depended on the initial EPSP size (Fig. 2, Table 2).
In the first group, TBS had a weak depolarizing action
(n = 5) (Fig.
2A1,B1).
A few spikes could be elicited in the first TBS burst in three of five
cells, and depolarization tended to decrease in subsequent bursts
(Fig. 2). After TBS, EPSP amplitude increased over control values by
23 ± 14% (n = 5; p < 0.01) in 15 min (Fig. 2A1,C).
In a second group, TBS caused a strong granule cell excitation
(n = 5) (Fig.
2A2,B2).
Robust action potential discharge was generated in all TBS bursts (Fig.
2). After TBS, EPSPs increased by 84 ± 16%
(p < 0.01; n = 5) over control
values in ~7 min, and most of them then elicited action potentials
(Fig. 2A2,C). In a
different set of cells showing strong TBS (n = 8),
action potentials were occasionally generated by control EPSPs (19.7%)
and became more frequent after LTP, precluding EPSP changes from being
measured. In these recordings, after TBS, the probability of action
potential generation increased by 120 ± 85% over control values
in 15 min (p < 0.01; n = 8)
(Fig. 2D), and in many cases spikes occurred in
doublets or triplets (data not shown).
Thus, although EPSP potentiation was observed in all cases, it was of
different magnitude depending on the initial EPSP size and the
excitatory action of TBS (see also below). It should be noted that
control EPSPs tended to decrease slightly with time (17.2 ± 11.4% after 20 min recordings; n = 5) (Fig.
2C), probably reflecting simultaneous synaptic depression
(Pockett et al., 1990; Christofi et al., 1993).
Potentiation of intrinsic membrane excitability
Cerebellar granule cells injected with step depolarizing currents
showed inward rectification in the subthreshold membrane potential
region and, once the threshold was reached, generated a repetitive
spike discharge (D'Angelo et al., 1995, 1998) (Fig. 3A). After TBS, action
potential generation was enhanced, and enhanced depolarization
associated with membrane potential oscillations could often be observed
in the threshold region (Figs. 3B, 5B, 7A). The current needed to generate spikes (current
threshold) decreased (Fig. 3A,B),
becoming significantly smaller than in control recordings (70 ± 16% 15 min after TBS; n = 10; p < 0.03) (Fig. 3C). Because GABA-A receptors were blocked, the
reduction in current threshold reflected a potentiation of intrinsic
granule cell excitability. The mechanism of excitability potentiation was further investigated by measuring changes of apparent granule cell
input resistance (Rin) and of action
potential threshold in the experiments of Figure 2C (those
in Fig. 2D had a similar behavior; data not
shown).
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Figure 3.
Enhanced action potential generation during LTP.
Granule cell responses to current injection (bottom
tracings, 2 pA/step) from 80 mV are compared in
(A) control recordings and in
(B) recordings in which LTP was induced (this
cell was one of those included in Fig.
2A1). Tracings were taken 8 and 25 min after the beginning of recordings. C, Time course of the
current needed to fire action potentials (current threshold) in control
recordings (; n = 5) and in recordings in which LTP
was induced (; n = 10). Note the marked decrease
in current threshold during LTP.
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Rin was measured from membrane
potential changes caused by current steps in the 10 mV potential range
either below or above 80 mV (Fig.
4A,B).
After TBS, Rin rapidly increased above
80 mV, whereas Rin remained
unchanged below 80 mV (Fig. 4C). The Rin increase reached 37 ± 33%
15 min after TBS (n = 10; p < 0.03).
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Figure 4.
Increased input resistance during LTP.
A, B, Voltage-current plots have been
constructed by measuring steady-state depolarization in the tracings of
Figure 3, A and B, respectively ( 8 min and 25 min after beginning of recordings). C,
Time course of Rin in control recordings
(dotted line, n = 5; SD was between
0.5 and 0.7 G) and in recordings in which LTP was induced
(solid line; n = 7). Note that after
LTP induction, Rin increased at potentials
higher (54) but not lower (55) than 80 mV. In control recordings
Rin remained stable in both potential
ranges.
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Action potential threshold was measured both at the beginning of spike
prepotential (Th1) and at the
beginning of upstroke (Th2) (Fig.
5, inset) (D'Angelo et al.,
1998). After TBS, both thresholds decreased, becoming significantly
lower than in control recordings (n = 10;
p < 0.05) (Fig. 5A-C). Because
Th1 decreased more than
Th2 (Fig. 5C), the spike
prepotential was enhanced (4.1 ± 3.2 mV 15 min after TBS;
n = 10; p < 0.03) (Fig.
5D).
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Figure 5.
Decreased spike threshold during LTP.
The inset shows where the thresholds of spike
prepotential (Th1) and spike upstroke
(Th2) were measured. A,
B, Spikes in control recordings (A) and
in recordings in which LTP was induced (B).
Tracings were taken 8 and 25 min after beginning recordings from the
same cells shown in Figure 3. C, Time course of
threshold changes in control recordings (n = 5;
dotted line; the SD was between 4 and 6 mV) and in
recordings in which LTP was induced (n = 10).
D, Greater decrease in Th1
than Th2 caused an enlargement of spike
prepotential during LTP (; n = 10; control
recordings 35; n = 5).
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These results indicated that an increase in
Rin and a decrease in spike threshold
combined to reduce the current needed to fire action potentials during
LTP (similar results could be obtained using CS rather than TBS) (Table
1).
Relationship between potentiation of EPSPs and
intrinsic excitability
The relationship between Rin and
EPSP potentiation is shown in the plot in Figure
6A, in which the
diagonal represents an equal increase in EPSP and
Rin. The presence of points either above or below the diagonal indicated that the
Rin increase could be associated with
an increase or decrease in synaptic conductance, respectively.
Moreover, points falling on the y-axis reflected a pure
synaptic conductance increase. It should be noted that points falling
above the diagonal were more frequently observed after strong (Fig.
6A, ) rather than weak (Fig. 6A,
) TBS bursts. Strong TBS should therefore be needed to obtain a
reliable synaptic conductance potentiation (also see Fig. 9).
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Figure 6.
Relationship between EPSP and intrinsic
excitability potentiation. A, Plot of EPSP versus
Rin changes at potentials higher than 80
mV. The diagonal is the place where EPSP equals
Rin changes, corresponds to weak TBS
(same experiments as in Fig.
2A1,B1), and corresponds to strong TBS (same experiments as in Fig.
2A2,B2). B,
Plot of EPSP versus Th1 ( , strong TBS,
n = 5;  , weak TBS, n = 5)
and Th2 ( , strong TBS,
n = 5;  , weak TBS, n = 5)
changes. Th1 and
Th2, which were measured in the same
cells included in Figure 2C and Table 2, were corrected
for time-dependent changes in control recordings. Note that changes in
Rin,
Th1, and
Th2 were already appreciable, with
relatively small EPSP changes. All data in this figure were recorded 15 min after TBS.
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The relationship between the spike threshold and EPSP potentiation
(Fig. 6B) showed that the spike threshold was
significantly reduced after either weak or strong TBS (Fig.
6B). Thus, as with the
Rin increase, the decrease in spike
threshold occurred at a lower threshold than potentiation of synaptic transmission.
Effect of synaptic inhibition on LTP
An important role in LTP regulation is played by inhibitory
synapses. In the hippocampus, synaptic inhibition has the dual role of
preventing LTP induction (Davies et al., 1991) and enhancing postsynaptic responsiveness through its own depression during LTP
(Abraham et al., 1987; Chavez-Noriega et al., 1990; Breakwell et
al., 1995). In the cerebellum, LTP properties may be regulated by
inhibitory Golgi synapses (compare Fig. 1).
Figure 7A shows recordings
from a granule cell in which TBS was delivered in bicuculline-free
solution to allow synaptic inhibition of the granule cell. In this
condition, TBS caused very weak depolarization, and no LTP was induced.
After 10 µM bicuculline perfusion, TBS caused
robust action potential discharge, inducing normal LTP. Average results
obtained in five recordings in bicuculline-free solution are shown in
Figure 7B,C. Burst membrane
potential during TBS settled at 2.1 ± 9.2 mV (n = 5), close to the Cl reversal
potential. EPSP, Rin, and spike
threshold showed no significant potentiation. GABA-A receptor-mediated
synaptic inhibition therefore exerted strong preventative action on
mossy fiber-granule cell LTP (similar results were obtained using CS
rather than TBS) (Table 1).
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Figure 7.
Synaptic inhibition prevents LTP. Effect
of TBS during perfusion of a bicuculline-free solution. A, B,
Tracings in A [EPSPs (top row)
and responses to 4 and 8 pA current steps (bottom row);
indicates application of TBS] and B (membrane
depolarization during TBS) illustrate one of two experiments in which
recordings lasted long enough to allow a second TBS to be applied
during subsequent 10 µM bicuculline perfusion. LTP,
comprising EPSP and intrinsic excitability potentiation, could be
elicited in the presence but not in the absence of bicuculline.
C, Average EPSP changes in six cells after TBS in
bicuculline-free solution. D, Rin
changes (both above and below 80 mV) and changes in
Th1 and Th2
corrected for time-dependent changes in control recordings. All data
were recorded 15 min after TBS (same cells as in
C).
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The role of membrane depolarization
Membrane depolarization is a fundamental factor in the induction
of synaptic plasticity (Kelso et al., 1986). Indeed, the results
reported in Figures 2 and 7 suggest that membrane depolarization during
TBS plays an important role in the subsequent potentiation of EPSPs and
intrinsic excitability. The effect of membrane depolarization was
further investigated by delivering TBS from a hyperpolarized membrane
potential (90 mV) (Fig.
8A). During TBS (Fig.
8B), burst membrane potential settled at 71.1 ± 3.2 mV (n = 6). After TBS, EPSPs tended to decrease
(Fig. 8C,D), although the change was not
statistically significant (p > 0.3).
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Figure 8.
Membrane hyperpolarization prevents LTP.
Effect of TBS delivered from 90 mV (10 µM bicuculline
in the bath). A, EPSPs recorded before and after TBS.
B, Membrane depolarization during TBS. Note that TBS
does not reach spike threshold. C, Average EPSP changes
in five cells after TBS. The control dotted lines are
replotted from Figure 2C. D,
Rin changes (both above and below 80 mV)
and changes in Th1 and
Th2 corrected for time-dependent changes in
control recordings. All data were recorded 15 min after TBS (same cells
as in C).
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When the effect of membrane depolarization in different experimental
conditions was considered (Fig.
9A1), a
direct relationship between mean TBS burst depolarization and the
magnitude of EPSP potentiation was observed. Potentiation of intrinsic
excitability (Fig. 9B1) showed a lower
threshold than potentiation of EPSP or synaptic conductance, as also
suggested by the plot in Figure 6A. As well as
membrane depolarization, the spikes may themselves enhance the
induction of synaptic plasticity (Thomas et al., 1998; Linden, 1999).
Optimal EPSP potentiation was associated with high spike frequency
(Fig.
9A2,B2),
whereas intrinsic excitability was already potentiated to the maximum
at low spike frequency. The implications of membrane depolarization and
spike discharge for mossy fiber-granule cell plasticity are considered
in Discussion.
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Figure 9.
LTP dependence on voltage and spike
frequency. A1, Magnitude of EPSP amplitude
changes as a function of depolarization (A1) or
spike frequency (A2) during TBS.  , Strong TBS
in 10 µM bicuculline (as in Fig.
2A2); , weak TBS in 10 µM
bicuculline (as in Fig. 2A1); , TBS in
bicuculline-free solution (as in Fig. 7); , TBS from 90 mV in 10 µM bicuculline (as in Fig. 8). In
A1, synaptic current changes in voltage-clamp
recordings with pairing at 60 or 40 mV are shown for comparison
( ) (data from D'Angelo et al., 1999). B1,
B2, Normalized changes in EPSP (solid
line), Rin (dashed line), and
spike threshold (Th1; dotted line) as
a function of depolarization (B1) or spike
frequency (B2) during TBS. EPSP and
Th1 data have been adjusted for
time-dependent changes in control recordings. Note that changes in
Rin and Th1 occur
earlier than those in EPSPs. All data in this figure were recorded 15 min after TBS.
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The role of NMDA receptors
Voltage-dependent NMDA receptor activation is the principal factor
responsible for LTP induction (Bliss and Collingridge, 1993). It was
therefore interesting to investigate whether potentiation of both EPSP
and intrinsic granule cells excitability depended on NMDA receptor
activation. Application of the NMDA receptor blockers, 100 µM APV and 50 µM 7-Cl-kyn (Fig.
10), depressed EPSP temporal summation
(Fig. 10B1) (D'Angelo et al.,
1995). During TBS applied from 70 mV, spike threshold was reached in
three of six cells. In the remaining three cells, mean burst
depolarization was 57.5 ± 6.5 mV (n = 3). None
of these cells showed any potentiation of EPSPs or intrinsic
excitability (compare Fig. 9). In an additional four experiments (Fig.
10A2), membrane depolarization was
reinforced by associating TBS with depolarizing current pulses (Fig.
10B2). In these experiments neither
EPSP nor intrinsic excitability potentiation were induced. The
cumulative results of the experiments in Figure 10, A and
B, are shown in Figure 10, C and D.
These results indicate that although NMDA receptors reinforce membrane
depolarization during repetitive stimulation, they are needed to induce
potentiation of EPSPs and postsynaptic responsiveness through a
mechanism that differs from their direct depolarizing action and
presumably involves an increase in Ca2+
influx and the consequent activation of
Ca2+-dependent processes.
View larger version (22K):
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|
Figure 10.
NMDA receptor block prevents LTP. Effect of TBS
delivered from 70 mV in the presence of 100 µM APV and
50 µM 7-Cl-ky to block NMDA receptors (10 µM bicuculline in the bath). A1,
A2, EPSPs recorded before and after TBS shown in
B1 and B2.
Although a normal TBS was applied in
B1, TBS was reinforced in
B2 by a 10 pA pulse during synaptic
activation. C, Average EPSP changes after TBS in six
cells as in A1 and
B1 and in four cells as in
A2 and
B2. D,
Rin changes (both above and below 80 mV)
and changes in Th1 and
Th2 adjusted for time-dependent changes in
control recordings. All data were recorded 15 min after TBS (same cells
as in C).
|
|
| |
DISCUSSION |
This paper demonstrates the potentiation of intrinsic excitability
in cerebellar granule cells after high-frequency mossy fiber
stimulation. The apparent input resistance
(Rin) increased and spike threshold
decreased, enhancing granule cell synaptic excitation. Potentiation of
intrinsic excitability could coexist with potentiation of synaptic
efficacy, and both depended on NMDA receptor activation.
Potentiation of granule cell intrinsic excitability was induced between
60 and 40 mV. In this potential range, granule cell NMDA receptors
activate sizeable conductance (D'Angelo et al., 1995), probably
because the NR2C subunit confers low sensitivity to
Mg2+ block (Monyer et al., 1994). The main
action of NMDA receptors could be that of gating
Ca2+ influx (in fact, in whole-cell
recordings performed with pipettes containing 10 mM BAPTA,
any excitability change was prevented; n = 5) (E. D'Angelo and P. Rossi, unpublished observation). In addition, NMDA
receptors enhanced membrane depolarization (Fig. 10).
Synaptic conductance needed stronger depolarization (approximately 40
mV) than intrinsic excitability to be potentiated [see also D'Angelo
et al. (1999)]. A discriminating factor between these two aspects of
potentiation may be the intensity of the NMDA current, which rises
steeply between 60 and 40 mV. Another discriminating factor may be
spikes (Thomas et al., 1998; Linden, 1999). Spikes were frequent when
LTP included synaptic conductance potentiation, whereas they were rare
or absent when potentiation of intrinsic excitability was prominent.
Spikes may favor the induction of plasticity through a
Na+-dependent enhancement of the NMDA
current (Yu and Salter, 1998) and by activating voltage-dependent
Ca2+ channels (Magee and Johnston, 1997;
Markram et al., 1997; Aizenmann et al., 1998; Aizenmann and
Linden, 2000). It should be noted that spikes alone were not
sufficient to induce synaptic plasticity, as demonstrated by recordings
in which NMDA receptors were blocked.
The control of granule cell synaptic excitation proved critical in
allowing a voltage- and NMDA receptor-dependent regulation of
plasticity. On the one hand, granule cell excitation was finely modulated by the intensity [and frequency; see D'Angelo et al., 1995)
of repetitive mossy fiber discharge. The physiological significance of
this mechanism is suggested by the observation that repetitive mossy
fiber discharge changes in relation to specific behavioral states
in vivo (Kase et al., 1980; Pellerin and Lamarre, 1997; Hartmann and Bower, 1998). On the other hand, granule cell
excitation was reduced through both tonic and phasic mechanisms of
synaptic inhibition mediated by Golgi cells (Fig. 1) (Brickley et al., 1996). Although Golgi cell inhibition prevented mossy fiber-granule cell plasticity, the efficiency of this process in vivo
remains speculative. Golgi cell activity reflects excitation in a large population of mossy and parallel fibers (Eccles et al., 1967; van Kan
et al., 1993; Vos et al., 1999), the discharge of which is probably
less synchronous than in our experiments (in which the whole afferent
fiber bundle was excited). Thus Golgi cells should dynamically modulate
mossy fiber-granule cell plasticity rather than exert an all-or-none
preventative action. Moreover, local depression of GABA release by
high-frequency mossy fiber discharge (Mitchell and Silver, 2000) may
favor LTP induction at specific synapses by contrasting background
granule cell inhibition (Davies et al., 1991). A closer understanding
of Golgi cell functions seems crucial to clarify the physiological
induction mechanism of mossy fiber-granule cell plasticity.
The increase in granule cell input resistance and spike prepotential
occurred in a limited membrane potential region, suggesting that
voltage-dependent conductances involved in spike generation were
changed. Although at present there is no direct evidence to implicate
any specific membrane conductance, it should be noted that an increased
Na+ current and a decreased
K+ current may account for a reduced
firing threshold, as demonstrated recently in cell culture (Desai et
al., 1999). A Ca2+ current-dependent
effect, which might occur in hippocampal pyramidal neurons
(Wathey et al., 1992) or in cerebellar deep nuclear cells (Aizenmann and Linden, 2000), seems less likely to occur in
cerebellar granule cells because their
Ca2+ currents activate once the spike has
already been generated (D'Angelo et al., 1998). It should be noted
that persistent depression of synaptic inhibition (as reported in
hippocampal E-S potentiation) (Abraham et al., 1987; Chavez-Noriega e
al., 1990; Breakwell et al., 1995) did not significantly contribute to
enhance granule cell excitation.
Potentiation of intrinsic excitability and synaptic conductance
cooperated to strengthen EPSP-spike coupling and to increase the
reliability of spike generation during synaptic transmission (Daoudal
et al., 1999). However, the functional significance of intrinsic
excitability potentiation may differ partly from that of synaptic
conductance potentiation. First, because potentiation of intrinsic
excitability could be achieved at a relatively low threshold, it may
have a compensatory effect by restoring granule cell readiness in
conditions of weak synaptic excitation (Fregnac, 1998). An increased
excitability in turn may facilitate the subsequent induction of
synaptic conductance potentiation. Second, because the granule cell has
a compact electrotonic structure and a marginal potential loss is
expected from dendritic endings to soma (Gabbiani et al., 1994;
D'Angelo et al., 1995; Silver et al., 1996), potentiated excitability
should affect neuronal responsiveness as a whole. Conversely, synaptic
conductance changes are thought to be synapse specific (Bliss and
Collingridge, 1993).
By allowing learning and storage of activity patterns at specific
synapses while maintaining neuronal firing within an appropriate operating window, the combination of changes in synaptic conductance and intrinsic excitation may optimize information transfer and network
computation (Stemmler and Koch, 1999). Although plasticity at the mossy
fiber-granule cell synapse was not included in Marr's (1969) original
model of the cerebellum, it may have important implications for
cerebellar control of motor coordination (Arbib et al., 1998;
Schweighofer et al., 1998; N. Schweighofer, personal communication).
| |
FOOTNOTES |
Received Feb. 28, 2000; revised April 17, 2000; accepted April 25, 2000.
This work was supported by European Community Grants PL97 0182 and PL97 6060, and by INFM. We acknowledge Arianna Maffei and Elisabetta Sola for assistance with experiments.
Correspondence should be addressed to Dr. Egidio D'Angelo, Department
of Cellular/Molecular Physiology and Pharmacology, Via Forlanini 6, I-27100 Pavia, Italy. E-mail: dangelo{at}unipv.it.
| |
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P. Rossi, E. Sola, V. Taglietti, T. Borchardt, F. Steigerwald, J. K. Utvik, O. P. Ottersen, G. Kohr, and E. D'Angelo
NMDA Receptor 2 (NR2) C-Terminal Control of NR Open Probability Regulates Synaptic Transmission and Plasticity at a Cerebellar Synapse
J. Neurosci.,
November 15, 2002;
22(22):
9687 - 9697.
[Abstract]
[Full Text]
[PDF]
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G. Daoudal, Y. Hanada, and D. Debanne
Bidirectional plasticity of excitatory postsynaptic potential (EPSP)-spike coupling in CA1 hippocampal pyramidal neurons
PNAS,
October 29, 2002;
99(22):
14512 - 14517.
[Abstract]
[Full Text]
[PDF]
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A. Maffei, F. Prestori, P. Rossi, V. Taglietti, and E. D'Angelo
Presynaptic Current Changes at the Mossy Fiber-Granule Cell Synapse of Cerebellum During LTP
J Neurophysiol,
August 1, 2002;
88(2):
627 - 638.
[Abstract]
[Full Text]
[PDF]
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M. Ito
Cerebellar Long-Term Depression: Characterization, Signal Transduction, and Functional Roles
Physiol Rev,
July 1, 2001;
81(3):
1143 - 1195.
[Abstract]
[Full Text]
[PDF]
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B. D. Burrell, C. L. Sahley, and K. J. Muller
Non-Associative Learning and Serotonin Induce Similar Bi-Directional Changes in Excitability of a Neuron Critical for Learning in the Medicinal Leech
J. Neurosci.,
February 15, 2001;
21(4):
1401 - 1412.
[Abstract]
[Full Text]
[PDF]
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E. D'Angelo, T. Nieus, A. Maffei, S. Armano, P. Rossi, V. Taglietti, A. Fontana, and G. Naldi
Theta-Frequency Bursting and Resonance in Cerebellar Granule Cells: Experimental Evidence and Modeling of a Slow K+-Dependent Mechanism
J. Neurosci.,
February 1, 2001;
21(3):
759 - 770.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
