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The Journal of Neuroscience, March 1, 2003, 23(5):1622
Dopamine Modulation of Perisomatic and Peridendritic Inhibition
in Prefrontal Cortex
Wen-Jun
Gao,
Yun
Wang, and
Patricia S.
Goldman-Rakic
Department of Neurobiology, Yale University School of Medicine, New
Haven, Connecticut 06510
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ABSTRACT |
The computations underlying cognitive functions are performed by a
diversity of interactions between interneurons and pyramidal neurons
that are subject to modulatory influences. Here we have used paired
whole-cell recording to study the influence of dopamine on local
inhibitory circuits involving fast-spiking (FS) and non-FS cells,
respectively. We found that dopamine depressed inhibitory transmission
between FS interneurons and pyramidal neurons but enhanced inhibition
between non-FS interneurons and pyramidal cells. FS inhibitory
transmission exhibited properties associated with presynaptic action at
D1 receptors that were not evident in non-FS inhibitory
connections. In addition, FS and non-FS interneurons differed
morphologically, forming contacts on the perisomatic and peridendritic
domains, respectively, of their pyramidal cell targets. These findings
provide evidence for both a dual mode of inhibition in prefrontal
circuitry and circuit-dependent modulation by dopamine.
Key words:
dual whole-cell recording; GABA; local circuits; interneurons; dopamine; cortical slice
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Introduction |
The dopamine (DA) innervation
of the prefrontal cortex has been implicated both in the modulation of
normal cognitive processes, most particularly working memory, and in
numerous neurobiological diseases including Parkinson's disease,
age-related memory decline, and schizophrenia (Gotham et al., 1988 ;
Davis et al., 1991; Volkow et al., 1998; Mattay et al., 2002). The
prefrontal cortex receives a rich dopamine innervation from the ventral
tegmental area, forming synapses onto both pyramidal cells and
interneurons (Sesack et al., 1995; Krimer et al., 1997). We have shown
previously that recurrent excitatory transmission between pyramidal
cells in the prefrontal cortex is presynaptically depressed by dopamine
acting through the D1 receptor (Gao et al., 2001). However,
pyramidal cell excitability is also powerfully modulated by inhibitory
interneurons (Buhl et al., 1994; Thomson and Deuchars, 1997; Somogyi et
al., 1998; Xiang et al., 1998). Indeed, inhibitory processes have been shown recently to have an essential role in sculpting the spatial tuning and temporal dynamics of prefrontal neurons, because they are
engaged in mediating the working memory functions of the brain (Wilson
et al., 1994; Rao et al., 1999, 2000; Constantinidis et al.,
2002).
Inhibitory neurons in the cortex have been differentiated on the basis
of their firing patterns in response to depolarizing current pulses and
their patterns of dendritic and axonal arborizations (Kawaguchi, 1995;
Kawaguchi and Kubota, 1997; Somogyi et al., 1998; Gupta et al., 2000).
Although there is as yet no universally agreed on classification of
cortical interneurons, it is widely accepted that fast-spiking (FS)
interneurons can be distinguished from non-FS cells such as regular
spiking (RS), low-threshold spiking (LTS), and late-spiking (LS) cells
(Kawaguchi and Kubota, 1997; Gibson et al., 1999). In addition, it has
been established that FS inhibitory neurons preferentially innervate
the soma or the axonal initial segment of pyramidal cell targets to
control action potential initiation, whereas other interneurons
primarily regulate dendritic excitability and the efficacy of
excitatory inputs (Freund and Buzsaki, 1996; Somogyi et al., 1998).
The effects of dopamine on inhibitory neurons have been studied
extensively in the striatum and nucleus accumbens (for review, see
Nicola et al., 2000; Bracci et al., 2001) and in subicular neurons
(Behr et al., 2000) with extracellular stimulation methods. These studies have revealed that DA can exert significant effects on
the activity of individual cells in the striatum and nucleus accumbens
by a number of different mechanisms, including modulation of
voltage-dependent conductances and effects on excitatory and inhibitory
synaptic transmission. Using similar methods, the actions of dopamine
on inhibitory transmission in the cerebral cortex indicate that
dopamine also inhibits evoked IPSCs in the prefrontal cortex
(Gonzalez-Islas and Hablitz, 2001; Seamans et al., 2001). However,
considering the physiological and morphological diversity of
interneurons in the neocortex (Kawaguchi, 1995; Kawaguchi and Kubota,
1997; Gupta et al., 2000), it is possible that the effects of dopamine
are not uniform on all interneuron subtypes. To examine this
possibility, we have used paired whole-cell recording of synaptic
connections followed by morphological analysis to identify the
presynaptic origin of unitary IPSPs. Here we report evidence that
dopamine modulates inhibitory transmission in a circuit-dependent manner.
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Materials and Methods |
Slice preparation and physiological recording.
Methods for slice preparation and whole-cell recording from visualized
neurons have been described previously (Gao et al., 2001). In brief,
300-µm-thick horizontal slices from young adult ferret (3-4 months
of age) prefrontal cortex were cut with a microslicer in ice-cold
oxygenated artificial CSF (ACSF) containing (in
mM): 124 NaCl, 2.5 KCl, 1.25 NaH2PO4, 2 CaCl2, 1 MgSO4, 26 NaHCO3, and 10 dextrose, pH 7.4. The slices were
incubated in ACSF at 35°C for 1 hr and then kept at room temperature
until being transferred to the recording chamber. Slices submerged in
the recording chamber were perfused with oxygenated and prewarmed ACSF
(2 ml/min). The recordings were conducted at 32-34°C. Dual
whole-cell recordings in current-clamp mode were used for analysis of
connections between interneurons and pyramidal cells (NP-P). The
resistances of patch pipettes were 5-10 M and filled with
intracellular solution containing (in mM): 114 K-gluconate, 6 KCl, 0.5 CaCl2, 0.2 EGTA, 4 ATP-Mg, 10 HEPES, pH 7.25, and 0.3% biocytin (Molecular
Probes, Eugene, OR). The signals were amplified and filtered at
2 kHz in bridge-balance mode and acquired on a computer at sampling
intervals of 20-100 µsec through a DigiData 1200B interface using
software pClamp 8.1 (Axon Instruments, Foster City, CA).
Access resistance was monitored continuously during recording.
Data analysis. The average IPSP amplitude and SDs of 20-40
traces were measured between the 10 msec interval before the onset of
the IPSP and a 5 msec interval at the IPSP peak using Clampfit software
(Axon Instruments). The IPSP amplitude was thus defined as
the difference between two window averages. Background noise was also
measured in the same manner but with the two average windows shifted to
~30 msec before the elicited response (Stricker et al., 1996).
Three analyses were used to assess possible presynaptic and/or
postsynaptic mechanisms. First, the percentage of synaptic failure to
the evoked presynaptic spike was determined individually for each
recording. Failure was defined as an event in which the IPSP amplitude
was below the limit of 1.6× noise (rms). Second, we obtained a
paired-pulse ratio (PPR) by measuring the ratio of the first two
successive responses (second IPSP to first IPSP) of five responses to
pulses given at an interval of 100 msec (10 Hz). Third, a coefficient
of variation (CV) of IPSP amplitude was calculated as described by
Kullman (1994). The mean and SD (Mean IPSP and
SDIPSP) were calculated for the IPSP amplitudes recorded during 40 successive sweeps in most cases (27 of 30; 90%).
The CVs for control and during dopamine application were therefore
computed as
SDIPSP/MeanIPSP. Other
measurements included IPSP latency, 20-80% rise time, decay time
constant ( ), resting membrane potential, and spike threshold of
interneurons. The time constant was fit from the repolarization curve
of unitary IPSPs by using a standard exponential formula in Clampfit
(Axon Instruments). Membrane potentials were not corrected for liquid
junction potentials. The data are analyzed by either ANOVA or
Student's t test and are presented as mean ± SE.
To examine whether dopamine modulation is cell-type specific, all of
our presynaptic interneurons were classified into FS and non-FS groups.
FS interneurons were easily identified by their narrow action
potentials, deep and brief afterhyperpolarization (AHP), and high
firing rates (100-150 Hz) with little or no frequency adaptation. The
non-FS class included RS, LTS, and LS, per the criteria described by
Kawaguchi (1995) and Gibson et al. (1999). LTS neurons had broader
spikes, pronounced adaptation of firing frequency, and more
specifically, low-threshold spikes when depolarized from more negative
potentials. At threshold stimuli level, RS cells fired regular spikes
with prominent firing spike adaptation and wide spikes (usually
half-width of >0.6 msec) (Kawaguchi, 1995; Gibson et al., 1999).
Drug application. Because dopamine can depolarize or
hyperpolarize both pyramidal neurons and interneurons, especially
depolarizing FS interneurons (Zhou and Hablitz, 1999), we recorded the
IPSPs at the subthreshold potential level ( 47 to 62 mV; average,
52.9 mV). However, the membrane potential was always kept constant before and during dopamine application for individual experiments. Dopamine was applied either in puff through a glass pipette (tip diameter, ~1-2 µm; concentration, 0.1-10
mM; pressure, 6.9-13.8 Kp) or by bath (10-30
µM) with addition of the antioxidant ascorbic acid (10 µM). A D1-specific
dopamine receptor agonist
[2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393), 20-40 µM with 10 µM ascorbic acid] and antagonist [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390), 10-20 µM]
and a D2-specific agonist (quinpirole, 15-30
µM) and antagonist (raclopride, 10-20
µM) were bath perfused. To examine the
specificity of dopamine receptor modulation, other antagonists, such
as the  -2 adrenergic receptor antagonists Yohimbine (100 nM) or Prozasin (100 nM)
(Marek and Aghajanian, 1999) and the GABAB
receptor antagonist
3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P- benzyl-phosphinic acid (CGP55845; 1 µM)
were also bath applied. GABAA receptors were
blocked in some experiments with bath application of bicuculline
methiodide (5 or 10 µM).
Morphological analysis. Slices were immediately fixed in
cold 4% paraformaldehyde for 3-5 d after recording. The slices were directly reacted in 3% hydrogen peroxide for 25 min. After thorough rinsing, ABC reactions were conducted overnight, and then Ni-DAB was
reacted on the following day (Tamas et al., 1997; Krimer et al., 2001).
The slices were resectioned into either 150 or 60 µm sections. The
former were directly mounted from phosphate buffer and covered
with water-soluble mounting media for reconstruction, whereas the 60 µm sections were air-dried and mounted with Permount for cell-type
identification and photography. Morphological analysis was conducted by
one of the authors (Y.W.), who was blind to their physiological
properties. The 150 µm sections of recovered cells were viewed and
drawn on a MicroBrightField (Williston, VT) camera lucida
and classified on the basis of their axonal trajectories, distribution
of bouton on somata or dendrites, and dendritic arbors. Correlation of
these properties and physiological subtype was performed only after all
microscopic study was completed. Selected labeled cells were fully
reconstructed with Neurolucida software (MicroBrightField), and the
reconstructed neurons were edited in PhotoShop (Adobe Systems, San
Jose, CA). The putative synaptic contacts were identified under the
light microscope as described previously (Buhl et al., 1994; Tamas et
al., 1997; Gupta et al., 2000).
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Results |
Dual modes of inhibition and differential modulatory effects
of dopamine
Nonpyramidal interneurons were identified under
infrared-differential interference contrast videomicroscopy by
their typical round or oval soma and bipolar or multipolar dendritic
orientations, and further distinguished by their narrow action
potentials and fast repolarization (Kawaguchi, 1995; Kawaguchi and
Kubota, 1997; Gibson et al., 1999). Thirty-five NP-P pairs were
successfully recorded before, during, and after dopamine application.
Per the criteria described by Kawaguchi (1995) and Gibson et al.
(1999), we classified all of our presynaptic interneurons into FS and non-FS groups (Fig.
1A-D). FS cells were
easily recognized according to their narrow action potentials, deep and
brief afterhyperpolarization, and high firing rates with little or no
frequency adaptation (Fig. 1A). Non-FS cells formed a
more diverse group, which included RS (Fig. 1B), LTS,
and LS cells (see Materials and Methods). Twenty-one of the 35 presynaptic interneurons (60%) examined were of the FS type, whereas
the remaining 14 cells were classified as non-FS cells (seven RSs, six
LTSs, and one LS).
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Figure 1.
Firing patterns of two types of interneurons.
A, B, Current-clamp recordings from an FS
cell (A) and a non-FS interneuron
(B) during injection of depolarizing current
pulses of two intensities. Note the short afterhyperpolarization after
a spike and the repetitive high-frequency firing without adaptation in
the FS cell. In contrast, the regular spiking cell
(B) has prominent firing adaptation, a wider
action potential, and a lower firing frequency. C,
D, Samples of biocytin-labeled interneuron-pyramidal
cell pairs. The FS interneuron (C, arrow)
has clear multiple dendritic processes with characteristics of basket
cells, whereas the non-FS interneuron (D, arrow)
has vertically oriented dendrites characteristic of a double bouquet
cell. Scale bar, 50 µm.
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Application of dopamine over a range of concentrations, either by puff
or bath perfusion, revealed remarkably dichotomous effects on the IPSP
amplitudes of FS and non-FS NP-P connections (holding potential,
52.9 ± 0.06 mV; reversal
potential, 70.2 ± 0.56 mV) (Figs. 2A,B,
3A,B). Dopamine significantly
decreased the IPSP amplitude in each of 17 FS NP-P connections (94.4%)
and increased it in one such pair (n = 18; 38.6% ± 5.30; p < 0.001). Because dopamine enhances the
excitability of FS interneurons and increases spontaneous GABA release
(Zhou and Hablitz, 1999), it is possible that the depressing effects of
dopamine on IPSPs in pyramidal neurons could have resulted from
stimulation of GABAB receptors on interneuronal
terminals. To examine this possibility, we iontophoretically applied
GABA (10 mM, 50-100 nA, 10-20 msec) on six
pyramidal cell somata. Consistent with a previous study (Gonzalez-Islas
and Hablitz, 2001), the amplitudes of GABA-induced current observed in
pyramidal cells were unchanged by dopamine (data not shown). This
result is compatible with a direct effect of DA on GABA release at
presynaptic terminals.
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Figure 2.
Properties of IPSPs and dopaminergic modulation.
A, Action potentials were induced with current injection
into the presynaptic interneuron, and the resultant IPSP was recorded
in a postsynaptic neuron (average of 20 traces; hold of approximately
58 mV). B, Graph showing that the reversal potential
in this recording condition is approximately 70 mV. C,
D, Two different classes of dopaminergic modulation: an
FS NP-P connection with a large IPSP amplitude and a fast rise time
(C) and a non-FS NP-P connection with a smaller
IPSP amplitude and slower rise time (D).
E, IPSP amplitude change and interneuron classification
(FS, filled circle; non-FS, open circle).
Most of the FS NP-P pairs exhibit dopamine depression, whereas non-FS
NP-P connections show dopamine enhancement. F, Summary
of dopamine effects in FS and non-FS groups. Dopamine reversibly
decreased the IPSP amplitudes of the FS group by 38.6%
(n = 18; *p < 0.001) but
increased IPSP amplitudes in non-FS NP-P pairs by 44.7%
(n = 12; p < 0.001).
The two groups were significantly different, but both recovered after a
10 min wash. Note that all averaged IPSPs shown here and in the
following figures are without failures.
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Figure 3.
Differential effects of dopamine on FS NP-P and
non-FS NP-P connections. A, Dopamine effects in FS NP-P
(n = 18) and non-FS NP-P (n = 12) connections indicating that the IPSP amplitudes in the FS group
were significantly higher than those in the non-FS group
(p < 0.001). B, Similar
results were obtained with different dopamine concentrations and
application methods in each group. C, The IPSP rise
times (20-80%) of FS NP-P pairs were significantly shorter than those
of non-FS NP-P partners (*p < 0.01), indicating a
difference of synaptic locations.
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In contrast, IPSP amplitude was increased by dopamine in 11 non-FS NP-P
pairs (91.7%) while decreasing in one (n = 12, 44.7% ± 9.55; p < 0.01). The remaining five of the 35 pairs
studied exhibited little change (<10%; p > 0.05;
ANOVA) (Fig. 2C-F, Table 1).
In addition, under control conditions, the IPSP amplitudes of FS NP-P
pairs were significantly higher than those of the non-FS NP-P pairs
(0.69 ± 0.10 vs 0.30 ± 0.05 mV with failures;
0.80 ± 0.10 vs 0.36 ± 0.07 excluding failures;
p < 0.001) (Figs. 2C,D, 3A).
Both depressing and enhancing effects recovered within several minutes
after washout (2-3 min for puff application; 5-8 min for bath
application (Fig. 2C,D,F). Other contrasts between
the two classes of interneurons included differences in firing
threshold, resting membrane potential, and most importantly, AHP
of action potentials (Table 1).
Previous studies of interneuronal diversity in the neocortex and
hippocampus have observed higher IPSP amplitudes, faster rise times,
and lower failure rates in somatic targeting interneurons than in the
dendrite-targeting interneurons, which are subject to dendritic
filtering (Freund and Buzsaki, 1996; Miles et al., 1996; Jiang et al.,
2000). Because FS cells are primarily thought to be somatic targeting
or basket-type interneurons and non-FS cells are more likely to be
dendritic targeting interneurons (Kawaguchi, 1995; Thomson et al.,
1996), we examined rise times and failure rates in the FS NP-P and
non-FS NP-P pairs. Particular attention was given to rise time of
IPSPs, because this measure is the best biophysical indicator of the
mean electronic distance of synaptic inputs and has been shown to
correlate with the anatomically determined distance of synaptic
contacts (Buhl et al., 1994; Freund and Buzsaki, 1996; Miles et al.,
1996; Thomson et al., 1996; Maccaferri et al., 2000; but see Tamas et
al., 1997). We found that the FS NP-P connections had significantly
shorter rise times (3.44 ± 0.54 msec, 20-80% amplitude) (see
Materials and Methods) compared with the non-FS NP-P group (6.77 ± 1.11; p < 0.01) (Figs. 2C,D,
3C, Table 1), suggesting that the two types of inputs arise
from synaptic contacts with markedly different soma-dendritic locations on the postsynaptic neuron. Baseline failure rates also differentiated the pairs, being significantly lower in the FS NP-P pairs (average, 11.9 ± 2.50%) than in the non-FS NP-P group (34.6 ± 4.37%; p < 0.001) (Fig.
4A-C) and negatively
correlated with IPSP amplitudes (R2 = 0.448) (Fig.
4D). Moreover, dopamine increased the failure rate
threefold in FS NP-P pairs (p < 0.001) but
produced little or no change in the non-FS NP-P pairs (decrease, 7.1%;
p = 0.2380) (Fig. 4C, Table 1). Finally,
failure rate was also negatively correlated with the firing threshold
of the interneurons in both circuits (r = 0.601)
(data not shown), further implicating subtype specificity in the
interneuron and/or connectivity in each of these two groups.
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Figure 4.
Summary of synaptic failure rates and
correlation in two populations of interneurons. A,
B, Top, Action potentials of five
sweeps from a single interneuron of an FS NP-P and a non-FS NP-P pair.
Middle, Five representative traces and the average
of successful responses from one FS and one non-FS NP-P pair,
respectively, showing the synaptic failure before and during
dopamine application. Failures were not observed in the FS NP-P pairs
during control conditions but did increase under dopamine application.
In contrast, in the non-FS NP-P pairs, synaptic failures were observed
under control conditions, and their incidence was not affected by DA
application. Dashed lines indicate the onset of IPSPs.
C, The failure rate was significantly lower in the FS
group (11.9 ± 2.50%) than that in the non-FS group (34.6 ± 4.37%; p < 0.001) under control conditions.
Moreover, the two groups were differentially modulated by dopamine. The
failure rate in the FS group was significantly increased 21.5% by
dopamine (*p < 0.01) compared with little or no
change in the non-FS group. D, Failure rates in
two groups were negatively correlated with IPSP amplitude
(R2 = 0.448). This relationship
disappeared after application of dopamine (data not shown). Note the
electrical coupling between interneuron and pyramidal cell in
A and in Figure 6A.
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Correlation of dopaminergic modulation with interneuron type and
mechanism of action
The differential effects of dopamine on synaptic failure rate
change suggested that dopamine modulation of the two modes of inhibition might act through distinct mechanisms, presynaptic and
postsynaptic, respectively (Gao et al., 2001; Gonzalez-Islas and
Hablitz, 2001; Seamans et al., 2001). This hypothesis was tested in
paired-pulse experiments with 100 msec intervals (10 Hz). The majority
of FS NP-P pairs (8 of 13; 61.5%) showed paired-pulse depression
(PPD), and only a few (5 of 13; 38.5%) exhibited paired-pulse facilitation (PPF). Dopamine application significantly increased the
paired-pulse ratios in most of these pairs (10 of 13; p < 0.001) (Fig. 5A,B, Table
1), again supporting a presynaptic mode of action. In contrast,
paired-pulse ratios were unchanged in the five non-FS NP-P pairs tested
(n = 5; p = 0.532) (Fig.
5B,C, Table 1). Moreover, we computed the CV of IPSP
amplitude in individual recordings for all FS and non-FS NP-P pairs
(Kullman, 1994). Although the CV test is also dependent on the
signal-to-noise ratio, the advantage of this test is that it is based
on detecting a change in a measure reflective of the entire
distribution of IPSP amplitudes and is therefore more applicable to
small-amplitude IPSPs. As shown in Figure 5, D and
E, a low CV in FS NP-P connections under control conditions
was sharply increased on average by 39.5 ± 6.81% with dopamine
application (p < 0.001), compared with
virtually no change (8.5 ± 3.60%; p = 0.385)
in non-FS NP-P pairs. Moreover, the percentage of change in CV was
highly correlated with IPSP amplitude change
(R2 = 0.606) in the FS NP-P
pairs but not in the non-FS NP-P connections (R2 = 0.008) (Fig.
5E), further strengthening a differential mechanism of
dopamine action on FS and non-FS inhibitory circuitry.
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Figure 5.
Changes in PPR, CV, and correlation between CV and
IPSP amplitude change. A, B, Paired-pulse
ratio change in the FS and non-FS NP-P pairs. A majority of the FS NP-P
pairs tested (n = 13) exhibited paired-pulse
depression at 10 Hz. Dopamine increased the ratio of second IPSP to
first IPSP as presented in normalized traces in FS NP-P connections but
had no clear effect in non-FS NP-P pairs. C, Summary of
normalized PPR showing that dopamine significantly increased the ratio
by 27.7% (*p < 0.001) in FS NP-P connections; no
effect was seen for non-FS NP-P connections. D, Because
of the low failure rate and large IPSP amplitude in FS NP-P pairs, the
CV of IPSP amplitudes under control conditions was significantly lower
than that of non-FS NP-P pairs (*p < 0.001) and
was sharply increased by 39.5% (*p < 0.001). In
contrast, there was almost no change in the non-FS group.
E, The percentage of change in the CV in FS NP-P pairs
was highly correlated with the percentage of change in IPSP amplitude
(R2 = 0.606) compared with no
significant correlation in non-FS NP-P pairs
(R2 = 0.008). Note the different
scale in the x-axis.
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Dopamine receptor involvement in inhibitory modulation
Dopamine mediates its actions at D1 and D2
receptors. To determine which dopamine receptor was involved in the
observed effects, we applied D1 and D2 specific
agonists to FS NP-P and non-FS NP-P pairs. As shown in Figure
6, A and B, the
D1 agonist SKF 38393 induced depression of IPSPs to the
same degree as dopamine itself in the six FS NP-P pairs tested
(decrease 28.6%; n = 6; p < 0.05), whereas the D2 agonist quinpirole failed to induce any
effect (n = 5; p = 0.675). This finding
was confirmed by showing that dopamine failed to induce significant
inhibition in FS NP-P pairs in the presence of the D1
antagonist SCH 23390 (decrease, 11.6 ± 4.78%; n = 4; p = 0.327) (Fig. 6C,D), whereas its
action was unaffected by the D2 antagonist raclopride
(reduction of 31.7 ± 6.21%; n = 4;
p < 0.05). The effects of these drugs on non-FS NP-P
pairs were small and highly variable, and no conclusion could be
reached regarding the dopamine receptor(s) involved in their modulation.
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Figure 6.
D1 receptor modulation in
the FS NP-P pairs. A, B, Sample average
traces and histograms showing that the D1 agonist SKF 38393 (SKF; 30 µM bath) but not the
D2 agonist quinpirole (Quin; 20 µM) reversibly depressed IPSP amplitude. SKF 38393 significantly depressed IPSP amplitude by 28.6% (n = 6; *p < 0.05), whereas quinpirole had no clear
effect (n = 5; p = 0.675).
C, D, Example of a D1
antagonist, SCH 23390 (SCH; 10 µM),
blocking dopaminergic depression of inhibition in an FS NP-P pair. SCH
23390 partially blocked depression of IPSP by dopamine (SCH 23390, 10 µM; DA, 30 µM) compared with a lack of
effect with the D2 antagonist raclopride
(Rac; 10 µM). Although in the presence of
SCH 23390 (10-20 µM), dopamine still depressed IPSP
amplitude by 11.6%, this response was not significant
(n = 4; p = 0.327). In
contrast, the D2 antagonist raclopride (10-20
µM) was ineffective in blocking the depressive effect of
dopamine (reduction of 31.7%; n = 4;
*p = 0.021). E, The
GABAB antagonist CGP55845 (CGP; 1 µM) had no effect on control IPSP amplitudes or kinetics
of FS NP-P connections. In the presence of CGP55845, DA (30 µM bath) still depressed IPSP amplitudes by 21.5 ± 7.47% (n = 3). F, The selective adrenergic antagonists Yohimbine (Ymb; 100 nM) and Prozasin (100 nM) failed to block the
depressive action of DA on IPSP amplitudes in FS NP-P connections, even
when the dose of Yohimbine was 10 times higher than its
Ki value. DA (30 µM in bath)
still depressed IPSPs by 24.8 ± 5.55% in the presence of
Yohimbine (n = 4) and by 23.2 ± 3.42% in the
presence of Prozasin (n = 2) (data not
shown).
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Many different receptors have been implicated in the presynaptic
modulation of neurotransmitter release in the CNS (for review, see
Langer, 1997). Because in our experiments the D1 antagonist only partially blocked the depression of FS NP-P transmission caused by
dopamine, we tested whether other neurotransmitter receptors might be
involved in the modulatory effects observed. The
GABAB receptor and adrenergic -2 receptors
would be highly likely candidates for this effect, because both are
known to be located presynaptically (Aoki et al., 1998; Gonchar
et al., 2001; Raiteri, 2001). In addition, stimulation of the
GABAB receptor has been reported to depress IPSPs
in the nucleus accumbens (Uchimura and North, 1991; but see Nicola and
Malenka, 1997). Therefore, we applied the
GABAB antagonist CGP55845 at a concentration (1 µM) that has been reported previously (Nicola and
Malenka, 1997) on three FS NP-P pairs. In none of these pairs
was there evidence of an effect on IPSP amplitudes or kinetics, and
moreover, bath perfusion of DA (30 µM) in the presence of
CGP55845 still depressed IPSP amplitudes by 21.5 ± 7.47%
(n = 3) (Fig. 6E). This result is
consistent with previous reports by Nicola and Malenka (1997)
and Seamans et al. (2001). Both groups also found a lack of effect of
GABAB antagonists on DA actions in the nucleus
accumbens and prefrontal cortex, respectively. Noradrenaline and
-adrenergic agonists have also been shown to depolarize FS
interneurons in the frontal cortex (Kawaguchi and Shindou, 1998).
However, we found that the selective -adrenergic antagonists
Yohimbine (100 nM) or Prozasin (100 nM) (Marek and Aghajanian, 1999) did not block
the depressive action of DA on IPSPs between FS interneurons and
pyramidal cells in the four pairs examined. The IPSPs were depressed
24.8 ± 5.55% by dopamine in the presence of Yohimbine
(n = 4) (Fig. 6F) and 23.2 ± 3.42% in the presence of Prozasin (n = 2) (data not
shown). These results further support the involvement of D1
presynaptic actions on inhibitory transmission in prefrontal circuitry.
FS and non-FS NP-P pairs correlate with specific
morphological characteristics
The conclusion of physiological analysis was verified by
morphological examination of the biocytin-injected interneurons. The
processes of eight FS interneurons and six non-FS interneurons were
labeled sufficiently well to allow identification of their dendritic
and axonal arborizations. Sample biocytin-labeled FS and non-FS NP-P
pairs are shown in Figure 7, A
and B, along with their associated firing pattern and drug
effects. The three-dimensional reconstruction in Figure 7A
reveals that the axon of the FS interneuron formed 14 putative synaptic
contacts on the soma and proximal dendrites of its pyramidal cell
partner, with an average distance of 83 µm from the pyramidal soma.
All eight FS interneurons were morphologically identified as basket
cells on the basis of their axonal and dendritic arborizations (five
large basket cells, one small basket cell, and two nest basket cells).
Putative somatic synapses were also found in all of these pairs. The
non-FS interneuron shown in Figure 7B exhibited the regular
spiking firing pattern. The accompanying reconstruction revealed that
it was a bitufted cell with beaded axons that formed 25 putative
synaptic contacts primarily on the middle and distal dendrites of the
postsynaptic pyramidal neuron with which it interacted. The average
distance of these contacts from the soma of this pyramidal cell was 258 µm, the approximate location of layer V cells where excitatory thalamic and corticocortical afferents would be expected to be most
dense (LeVay and Gilbert, 1976; White, 1989). Six non-FS interneurons
that were successfully reconstructed include two bitufted cells, one
Martinotti cell, and two double bouquet cells. The one remaining cell
from this group was difficult to classify but primarily resembled a
nest basket cell as described by Gupta et al. (2000). In contrast to FS
interneurons, only one non-FS interneuron axon contacted the soma of a
pyramidal cell, and notably in this case, only one putative synapse was
observed.
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Figure 7.
Electrophysiological and morphological
characteristics of two neuronal pairs from an FS and non-FS NP-P group,
respectively. Three consecutive traces recorded from an FS cell
(A) and a non-FS (regular spiking) cell
(B) during injection of depolarizing current
pulses of three intensities are shown. A single spike induced by narrow
current injection in these two presynaptic interneurons elicited
correlated IPSPs in the A and B pair,
respectively. The two control IPSPs (white line)
exhibited distinct properties, as described in Figure 2, whereas DA
reduced the IPSP in the FS NP-P pair but enhanced it in the non-FS NP-P
pair. Computer reconstructions of these two biocytin-filled
interneuron-pyramidal pairs at two magnifications are shown. The
interneuron of the FS NP-P pair is a fast-spiking basket cell of the FS
type, which forms 14 putative synaptic contacts on the soma and
proximal dendrites of the pyramidal neuron (inset,
bottom left). The interneuron of the non-FS NP-P pair is
an accommodating bitufted cell of the non-FS type with a regular
spiking firing pattern. Its beaded axons form 25 putative synaptic
contacts primarily on the middle and distal dendrites of the
postsynaptic pyramidal neuron with which it interacted
(inset, top right). Light
blue, Somata and dendrites of the pyramidal neuron;
blue, axons of the pyramidal neuron;
yellow, axonal arbors of the presynaptic interneuron;
orange, dendrites of this interneuron. Scale bar, 100 µm; A, inset, 50 µm;
B, inset, 40 µm.
Asterisks indicate putative synaptic contacts.
|
|
| |
Discussion |
The present study is the first paired recording study of
inhibitory transmission in the prefrontal cortex and the first to demonstrate that FS interneurons, which target the perisomatic domain
of pyramidal cells, are inhibited by dopamine, whereas non-FS
interneurons targeting more distal dendrites are not depressed, but
instead show a significant enhancement by this neuromodulator. This
difference between FS NP-P and non-FS NP-P pairs was demonstrated electrophysiologically and confirmed by morphological identification of
the presynaptic interneuron type. In the process of studying dopamine
regulation, we also provide the first direct evidence for perisomatic
and peridendritic inhibitory transmission in a cortical area involved
in working memory functions, thereby extending the generality of
circuit mechanisms initially discovered in other regions of the brain
(Freund and Buzsaki, 1996; Somogyi et al., 1998; Maccaferri et al.,
2000).
FS and non-FS modes of inhibition in prefrontal cortex
The classification of interneurons in this study was based on
generally accepted criteria for FS interneurons: narrow action potentials, deep afterhyperpolarizations, and high firing frequency with little or no frequency adaptation (Kawaguchi, 1995; Gibson et al.,
1999). Although these criteria are similar to those of Kawaguchi (1995)
and Gibson et al. (1999) in all critical respects, we, like others, did
not observe the slow depolarizing voltage ramp with abrupt onset and
offset of action potentials reported by Kawaguchi (1995) and Gibson et
al. (1999), indicating that this property may not be an obligatory
feature of FS cells (Connors and Gutnick, 1990; Buhl et al., 1996;
Thomson et al., 1996). Also, consistent with our previous studies in
prefrontal cortex (Krimer and Goldman-Rakic, 2001), the firing
frequency of our FS interneurons was considerably lower (100-150 vs
300 Hz), and the half-widths of action potentials were wider (0.53 vs
0.35 msec) than comparable values reported in other species and other
cortical areas (Kawaguchi, 1995; Buhl et al., 1996; Gibson et al.,
1999). Despite these differences, the validity of our classification is
strongly supported by biophysical properties such as rise times. IPSPs
evoked from non-FS interneurons had rise times nearly twice as long as
those evoked from FS interneurons. Although rise time may not be a
direct measure of differences in synaptic localization, the large
difference in this measure between the two subgroups of inhibitory
connections is consistent with a differential localization of their
synapses on pyramidal cells, in line with previous structure-function
correlations (Buhl et al., 1994; Freund and Buzsaki, 1996; Miles et
al., 1996; Thomson et al., 1996; Maccaferri et al., 2000).
Presynaptic versus postsynaptic mechanisms of
dopaminergic modulation
Paired recording in this study allowed us to identify the
presynaptic member of the recorded pairs and to examine possible distinctions between FS and non-FS inhibitory transmission on their
pyramidal cell partners. Indeed, differences between the two types of
circuitry were observed not only in IPSP amplitudes and rise times but
also in synaptic failure rates, paired-pulse ratios, and CVs. These
findings suggested that dopamine-mediated depression of inhibition
might involve a presynaptic mechanism, whereas the enhancing effects
are possibly postsynaptic. The presynaptic D1-mediated
depression observed is in agreement with the findings of Gonzalez-Islas
and Hablitz (2001), based on extracellular stimulation of prefrontal
neurons, but differs from that of Seamans et al. (2001). The
discrepancy is undoubtedly attributable to the different conditions in the study by Seamans et al. (2001), in which
the actions of dopamine were not immediate but emerged only several minutes after application and were mediated by D2. A
presynaptic mechanism for the inhibitory effect of dopamine on synaptic
transmission between FS interneurons and pyramidal cells is also
strongly supported by our recent finding that D1 receptors
are located on the axon terminals of interneurons (Muly et al., 1998).
The lack of effects on the depressive actions of presynaptic
autoceptor antagonists of DA (GABAB and -2
adrenergic) also supports D1 presynaptic modulation. Also
consistent with our results is a recent study showing that unitary
IPSCs between FS interneuron and pyramidal cells in the neocortex are
depressed by a kainate receptor agonist (Ali et al., 2001). As in the
present study, this effect was also accompanied by an increase in
failure rate, CV, and paired-pulse ratio.
A novel finding in this study is that dopamine enhanced inhibitory
transmission in non-FS NP-P connections. This acute effect was observed
without indications of altered presynaptic GABA release such as changes
in synaptic failure rate, paired-pulse ratio, and CV. Although the
mechanism of this effect remains to be determined, we speculate that
the enhancing effect of dopamine could occur via a postsynaptic action
(e.g., possibly because of a change of the electronic structure of the
postsynaptic neuron), a change in the voltage-dependent modulation of
local IPSPs, and/or an activation of some receptors such as
dopaminergic D2 receptor or -1 adrenoceptor. Dopamine is
well known to act on these receptors. It should be noted that non-FS
NP-P connections in layer V are particularly difficult to find (~1 in
every 50 recordings). Nevertheless, the relative change from control
levels in these circuits was substantial (~45%) and even larger than
the percentage of change observed in FS NP-P connections.
Unfortunately, the rarity of these connections curtailed our efforts to
characterize the dopamine receptor subtypes involved in this effect.
However, the differential effects of dopamine observed do indicate that
this neurotransmitter does not simply alter inhibition of pyramidal
neurons unidirectionally but selectively modulates GABAergic circuits
in the prefrontal cortex. Again, the morphological confirmation that FS
interneurons contacted soma and non-FS cells targeted dendrites further
supports the circuit dependency of the actions of dopamine in the
prefrontal cortex.
Functional implications
The present findings have implications for understanding the
role of dopamine in the working memory functions of the prefrontal cortex because they are expressed in the living animal. The signature functional property of dorsolateral prefrontal neurons recorded in vivo is the capacity for persistent activation in the
absence of a preferred stimulus (a property referred to as the memory field of the neuron) (Funahashi et al., 1989). Previous in
vivo studies in this laboratory have established that the spatial
tuning of these cells requires inhibition of inputs from nonpreferred stimuli (Funahashi et al., 1989; Rao et al., 1999, 2000). The dopamine
depression of FS-mediated somatic inhibition could serve to increase
the responsivity of a pyramidal neuron to its preferred excitatory
input by enhancing the repetitive discharge of sodium-dependent spikes
(Freund and Buzsaki, 1996; Yang and Seamans, 1996). Although the
mechanism underlying dendritic enhancement of inhibition is less clear,
enhancement of inhibition on dendrites could reduce the effectiveness
of inputs representing nonpreferred stimuli, a speculation that remains
to be examined. Accordingly, dopamine would simultaneously
promote the excitation of a pyramidal neuron by its preferred
sensory input through depression of somatic inhibition (by FS cells)
and at the same time reduce the effectiveness of nonpreferred stimuli
arriving at distal dendrites by shunting inhibition (by non-FS cells)
at these sites. Recording studies in behaving monkeys in this
laboratory have shown both that FS interneurons themselves are tuned
and that some of them have inverted tuning curves as would be suggested
by this model (Rao et al., 1999, 2000; Constantinidis et al., 2002).
Interneurons have been prominently implicated in disorders such as
epilepsy and schizophrenia, and understanding the mechanisms of their
modulation may contribute to a better understanding of pathophysiology
in these disorders.
| |
FOOTNOTES |
Received Aug. 30, 2002; revised Nov. 25, 2002; accepted Nov. 26, 2002.
This work was supported by National Institute of Mental Health Grant
MH44866/MH38546. We thank Anita Begovic for her expert technical
support. We are grateful to Drs. T. Koos, W. R. Chen, M. F. Yeckel, S. D. Antic, L. Negyessy, and X. J. Wang for reading this manuscript and for their critical comments.
Correspondence should be addressed to Dr. P. S. Goldman-Rakic,
Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510. E-mail:
patricia.goldman-rakic{at}yale.edu.
| |
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TOP
ABSTRACT
Introduction
