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The Journal of Neuroscience, September 1, 2002, 22(17):7509-7517
Activation of Presynaptic 5-Hydroxytryptamine 2A Receptors
Facilitates Excitatory Synaptic Transmission via Protein Kinase C in
the Dorsolateral Septal Nucleus
Hiroshi
Hasuo1,
Toshimasa
Matsuoka1, 2, and
Takashi
Akasu1
Departments of 1 Physiology and
2 Neuropsychiatry, Kurume University School of Medicine,
Kurume 830-0011, Japan
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ABSTRACT |
Effects of 5-hydroxytryptamine (5-HT) on EPSPs and
EPSCs in the rat dorsolateral septal nucleus (DLSN) were examined in
the presence of GABAA and GABAB receptor
antagonists. Bath application of 5-HT (10 µM) for 5-10
min increased the amplitude of the EPSP and EPSC.
(±)-8-Hydroxy-2-(di-N-propylamino)tetralin hydrobromide (10 µM), an agonist for 5-HT1A and
5-HT7 receptors, did not facilitate the EPSP.
 -Methyl-5-HT (10 µM), a 5-HT2 receptor
agonist, increased the amplitude of the EPSC.
-Methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (10 µM) and 6-chloro-2-(1-piperazinyl)pyrazine (10 µM), selective 5-HT2B and 5-HT2C
receptor agonists, respectively, had no effect on the EPSP. The
5-HT-induced facilitation of the EPSP was blocked by ketanserin (10 µM), a 5-HT2A/2C receptor antagonist.
However, N-desmethylclozapine (10 µM), a
selective 5-HT2C receptor antagonist, did not block the
facilitation of the EPSP induced by -methyl-5-HT. The inward current
evoked by exogenous glutamate was unaffected by 5-HT. 5-HT (10 µM) and -methyl-5-HT (10 µM) increased
the frequency of miniature EPSPs (mEPSPs) without changing the mEPSP amplitude. The ratio of the paired pulse facilitation was significantly decreased by 5-HT and -methyl-5-HT. The 5-HT-induced facilitation of
the EPSP was blocked by calphostin C (100 nM), a specific
protein kinase C (PKC) inhibitor, but not by
N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (10 µM), a protein kinase A inhibitor. Phorbol
12,13-dibutyrate (3 µM) mimicked the facilitatory effects
of 5-HT. These results suggest that 5-HT enhances the EPSP by
increasing the release of glutamate via presynaptic 5-HT2A
receptors that link with PKC in rat DLSN neurons.
Key words:
rat; dorsolateral septal nucleus; EPSP; mEPSP; paired
pulse facilitation; 5-HT2A receptor; synaptic facilitation; PKC; G-protein
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INTRODUCTION |
Principal neurons in the
dorsolateral septal nucleus (DLSN) receive glutamatergic nerve axons
from the hippocampal CA1 and CA3 regions via the fimbria-fornix
pathway and send axons to hypothalamic and amygdaloid areas (Alonso and
Frotscher, 1989 ; Gallagher et al., 1995; Jakab and Leranth, 1995).
Stimulation of the fimbria-fornix pathway evokes EPSPs followed by
IPSPs in DLSN neurons (Alonso and Frotscher, 1989; Gallagher et al.,
1995; Jakab and Leranth, 1995). DLSN neurons also receive nerve inputs
containing 5-hydroxytryptamine (5-HT) originating from the dorsal and
medial raphe nuclei (Köhler et al., 1982; Gall and Moore,
1984; Crunelli and Segal, 1985). Autoradiographic studies demonstrated
5-HT receptors, including 5-HT1-4 and
5-HT7 subtypes, with high-moderate levels in the
lateral septum (Biegon et al., 1982; Marcinkiewicz et al., 1984; Pazos
and Palacios, 1985; Pazos et al., 1985; Vergé et al., 1986;
Waeber et al., 1994; Gustafson et al., 1996; Morales et al., 1998).
Electrophysiological studies showed that ionophoretic application of
5-HT increases the excitatory component of the field potential evoked
in DLSN by electrical stimulation of the axons of hippocampal CA1 and
CA3 neurons (DeFrance et al., 1973). Intracellular studies showed that
activation of 5-HT1A receptors produced a
hyperpolarizing response (Joëls et al., 1987; Joëls and
Gallagher, 1988; Akasu et al., 2000) by activating inward and outward
rectifier K+ currents (Yamada et al.,
2001) in DLSN neurons. In addition, 5-HT strongly depressed the fast
and slow IPSPs via 5-HT1A receptors in the DLSN
(Joëls and Gallagher, 1988; Gallagher et al., 1995; Akasu et al.,
2000). In other brain regions, several studies have shown that 5-HT
depresses excitatory synaptic transmission (Segal, 1980; Bobker and
Williams, 1989; Mooney et al., 1994; Schmitz et al., 1995; Singer et
al., 1996; Li and Bayliss, 1998; Hwang and Dun, 1999) or enhances
neuronal excitability (Beck, 1992; Aghajanian and Marek, 1997).
However, little is known about the facilitation of excitatory synaptic
transmission by 5-HT except for spinal cord neurons (Hori et al.,
1996). In the present study, we examined the direct effect of 5-HT on
the EPSP (and EPSC) in the DLSN while inhibitory circuits were
pharmacologically eliminated. The results suggest that 5-HT
presynaptically enhances the EPSP (and EPSC) via
5-HT2A receptors and that the 5-HT-induced
facilitation of the EPSP is mediated by activation of protein kinase C
(PKC). A pertussis toxin (PTX)-insensitive G-protein, linked to
presynaptic 5-HT2A receptors, may be involved.
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MATERIALS AND METHODS |
Transverse brain slices containing the septal nuclei were
obtained in a manner described previously (Stevens et al., 1984). Briefly, male Wistar rats (120-200 gm) were killed by decapitation. Their brains were rapidly removed and immersed for 8-10 sec in cooled
artificial CSF (ACSF; 4-6°C) that was prebubbled with 95% O2 and 5% CO2. Brain
slices (400 µm in thickness) were cut with a Vibroslice (Campden
Instruments) and left to recover for 1 hr in oxygenated ACSF. The slice
was then transferred to a recording chamber and submerged in ACSF at
32-33°C. The composition of the ACSF was as follows (in
mM): 117 NaCl, 4.7 KCl, 2.5 CaCl2,
1.2 MgCl2, 25 NaHCO3, 1.2 NaHPO4, and 11 D-glucose, pH 7.4 and
295-305 mOsm. Intracellular recordings of the membrane potential of
DLSN neurons were made by using single glass microelectrodes filled with 3 M K-acetate (tip resistance, 80-140 M ). EPSPs
were evoked at 0.1 Hz by using a concentric bipolar electrode placed on
the fimbrial pathway. The perfusate routinely contained bicuculline (15 µM) and
(2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]- (phenylmethyl)
phosphinic acid (CGP 55845; 4 µM) to block
inhibitory postsynaptic responses unless otherwise stated (Gallagher et
al., 1995; Yamada et al., 2001). The intensity of the nerve stimulation was chosen to yield an EPSP that was one-half the size necessary to
activate an action potential (6-20 V for 200 µsec). Membrane potentials and currents were recorded with an Axoclamp-2A amplifier (Axon Instruments). Voltage-clamp recordings of the EPSC were made with
discontinuous single-electrode voltage-clamp mode at a sampling rate of
2-5 kHz and gain of 0.8 nA/mV. The head stage output was continuously
monitored. The efficacy of voltage clamp with a single microelectrode
ranged from 90 to 95% as estimated from the difference between the
clamped and unclamped EPSPs. The pClamp software program (Axon
Instruments) operating on a computer (Gateway) was used for later
analysis of the data. Unless otherwise stated, sample traces of
synaptic potential and currents represent averages of six consecutive
events. The miniature EPSP (mEPSP) was analyzed with minianalysis
software (Synaptosoft). Events were accepted for analysis when they had
amplitude of >0.2 mV, had a monophasic rising phase, and decayed to
baseline in an approximately exponential manner in 20 msec. In some
experiments, glutamate was applied to DLSN neurons by pressure pulses
(140 kPa for 30 msec) by using a Picospritzer (General Valve Co.,
Fairfield, NJ) from a glass pipette containing
L-glutamate (100 mM).
Experimental values are presented as the mean ± SE. Statistical
analyses were performed using Student's t test.
p < 0.05 was accepted as statistically significant.
Drugs were purchased from the following sources. 5-HT
creatinine sulfate complex was from Wako Pure Chemical Industries
(Osaka, Japan). ( )-Bicuculline methiodide, DNQX, AP-5,
N-ethylmaleimide (NEM), N-desmethylclozapine,
forskolin, (±)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide [(±)-8-OH-DPAT],
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635), phorbol 12,13-dibutyrate (PDBu),
N6,2'-O-dibutyryl-cAMP
(db-cAMP), and calphostin C were purchased from Sigma (St. Louis, MO).
Tetrodotoxin (TTX) was from Alomone Labs Ltd. (Jerusalem, Israel). CGP
55845, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP 93129), 4-amino-(6-chloro-2-pyridyl)-1-piperidine hydrochloride (SR
57227A), -methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (BW
723C86), 6-chloro-2-(1-piperazinyl)pyrazine (MK 212), -methyl-5-HT, (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide (WAY 100135),
1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-2-methylsulphonylamino]ethyl-4-piperidinyl]-1-propanone (RS 67506), 5-carboxamidotryptamine maleate (5-CT), and
3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4[1H,3H]-quinazolinedione (ketanserin) were from Tocris Cookson Ltd.
N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) was purchased from Seikagagu Corp. PDBu, CGP 55845, and BW 723C86 were dissolved in dimethylsulfoxide (DMSO) and added to
the ACSF, in which the final concentration of DMSO (0.1%) had no
direct effect on DLSN neurons. Other drugs were dissolved in the ACSF.
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RESULTS |
Effects of 5-HT on the evoked EPSP and EPSC in DLSN neurons
The resting membrane potential and input resistance of DLSN
neurons were 60 ± 0.5 mV (n = 73) and 119 ± 3 M (n = 73), respectively. Approximately 50% of
the neurons showed spontaneous firing at the resting membrane
potential. Figure 1A
shows the effects of 5-HT on spontaneous action potentials and EPSPs in
a DLSN neuron. Application of 5-HT to the bath produced a
hyperpolarizing response that completely blocked the spontaneous firing
(Fig. 1A1). However, the EPSP-mediated action
potential evoked by stimulation (10 V for 200 µsec) of the fimbrial
pathway was not blocked during the 5-HT-induced hyperpolarization (Fig.
1A2). We examined the direct effect of 5-HT (10 µM) on the EPSP in DLSN neurons, in which the membrane potential was initially held at 68-70 mV by injecting DC
current into the neurons. The hyperpolarizing response induced by 5-HT
(10 µM) was associated with a decrease in the
input membrane resistance (Fig. 1B). Pooled data
showed that 5-HT (10 µM) produced a 29 ± 5.9% (n = 16) decrease in the input membrane
resistance. The facilitation of the EPSP amplitude was clearly seen
when the 5-HT-induced hyperpolarization was nullified by injecting
depolarizing DC current (Fig. 1B2, b).
Pooled data showed that 5-HT (10 µM) produced a
36 ± 4% (n = 16) increase in the amplitude of
the EPSP. The EPSP recovered 10-40 min after removal of 5-HT from the
external solution, and the mean recovery time was 18 min (Fig.
1B2, d). The membrane potential and input
resistance of DLSN neurons recovered within 6 min after reapplication
of the ACSF (Fig. 1B3, c). In some neurons
that showed no obvious facilitation of the EPSP, the effect of 5-HT was
use-dependent. Figure
2A shows an example of
these experiments. A brief application of 5-HT (10 µM for 6 min) did not produce visible
facilitation of the EPSP. Subsequent exposure of DLSN neurons to 5-HT,
however, produced a clear facilitation of the EPSP (Fig.
2A). Furthermore, the enhanced EPSP lasted for >40
min even after removal of 5-HT from external solution. Statistical data
showed that the second application of 5-HT for 6 min produced 31 ± 2% (n = 4) facilitation of the EPSP (Fig.
2B).
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Figure 1.
Effects of 5-HT (10 µM) on
excitatory synaptic transmission and membrane properties of DLSN
neurons. The ACSF contained bicuculline (15 µM) and CGP
55845 (4 µM) to block IPSPs. A1,
Continuous chart recording of the membrane potential of a DLSN neuron.
The resting membrane potential was 58 mV. 5-HT was applied topically
at the time indicated by the filled triangle.
A2, Records a and b depict
three traces obtained before and after application of 5-HT at the time
indicated by open and filled circles in
A1, respectively. Open triangles indicate
time of fimbrial nerve stimulation. Note that action potentials were
elicited by enhanced EPSPs. Electrotonic potentials were produced by
applying rectangular current pulses (50 pA for 120 msec). The
dotted line indicates the original membrane potential
level. B1, Continuous chart recordings of the membrane
potential (top trace) and current (bottom
trace). The initial holding membrane potential was 70 mV. In
the top trace, upward and downward deflections represent
EPSPs and electrotonic potentials, respectively. The period of bath
application of 5-HT (10 µM) is indicated by the
horizontal bar. B2, Averaged six EPSPs
taken at the time indicated by the respective letters in
B1. In record c, the membrane potential
was returned to 70 mV by injecting outward DC current into the
neuron. Record f was taken 15 min after washout of 5-HT.
B3, Averaged six electrotonic potentials taken at the
time indicated by the respective letters in
B1. The electrotonic potentials were produced by
rectangular current pulses (50 pA for 150 msec).
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Figure 2.
Effects of repeated application of 5-HT on the
EPSP. A, Time course of the effects of repeated
application of 5-HT on the amplitude of EPSPs. 5-HT (10 µM) was applied to the bath for 6 min at the times
indicated by the open squares. Bottom
traces are sample records of the facilitation of the
EPSP induced by repeated application of 5-HT (10 µM).
Records a-d are recorded at the times indicated by the
respective letters on the graph. The
holding membrane potential was 68 mV. B, Pooled data
for the effects of 5-HT on the EPSP. Open and
hatched columns show first and second applications of
5-HT (10 µM). Abscissa, Percentage
facilitation of the EPSP amplitude. The number of experiments is shown
in parentheses. Error bars indicate SEM. *Statistical
significant (p < 0.01).
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Figure 3A shows the effect of
5-HT (10 µM) on the EPSC examined by using the
single-microelectrode voltage-clamp technique. Application of 5-HT (10 µM) produced an outward current with amplitude of 158 ± 12 pA (n = 17) at a membrane potential
of 70 mV (Fig. 3A, b). 5-HT (10 µM) increased the amplitude of the EPSP;
averaged amplitudes of 30 EPSCs obtained before and 5 min after
application of 5-HT (10 µM) were 125 ± 4 and 176 ± 8 pA, respectively, in this neuron (Fig.
3A). Pooled data showed that 5-HT (10 µM) produced a 39 ± 3%
(n = 11) increase in the amplitude of the EPSC. The facilitation of the EPSC amplitude by 5-HT was concentration-dependent. At a concentration of 1 µM, 5-HT produced a
visible (12 ± 4%; n = 10) facilitation of the
EPSC. At a concentration of 10 µM, the
facilitation of the EPSC reached its maximum within 5-6 min after
beginning of the application of 5-HT. Increased EPSCs returned to the
control level within 10-30 min after withdrawal of 5-HT from the ACSF.
The effect of -methyl-5-HT, a 5-HT2 receptor
agonist, on the EPSC was examined in voltage-clamped neurons (Fig.
3B). Bath application of -methyl-5-HT (10 µM) produced an outward current (118 ± 10 pA; n = 7). The averaged amplitudes of 30 EPSCs were
207 ± 8 and 309 ± 10 pA in the absence and presence of
-methyl-5-HT (10 µM), respectively. Pooled
data showed that -methyl-5-HT (10 µM)
produced a 49 ± 7% (n = 7) increase in the
amplitude of the EPSC. The changes in the membrane conductance reached
a maximum within 2 min after beginning of the application of 5-HT (10 µM). The conductance returned to the control
value within 5 min after washout of 5-HT (Fig. 2C).
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Figure 3.
Effects of 5-HT (10 µM) and
-methyl-5-HT (10 µM) on EPSCs in DLSN neurons. ACSF
contained bicuculline (15 µM) and CGP 55845 (4 µM) to block IPSPs in all experiments. Data points are
averages of six responses. Periods of drug application are indicated by
horizontal bars. Bottom traces in
A and B are sample records of neuron
responses at the times indicated by the corresponding
letters on the graph. Open
triangles indicate the time of fimbria stimulation.
A, Facilitation of the EPSC induced by 5-HT (10 µM) in a DLSN neuron voltage-clamped at -70 mV. The
dotted line indicates predrug membrane current (also in
B). B, Effects of -methyl-5-HT (10 µM) on the EPSC. Holding membrane potential was -70 mV.
C, Time course of the effects of 5-HT (3 µM) on the EPSC and the membrane conductance. The
membrane conductance was monitored via the change in inward currents
induced by hyperpolarizing voltage commands (10 mV for 80 msec). The
facilitation of the EPSC by 5-HT was preceded by the membrane
conductance change.
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Effects of BW 723C86, a selective 5-HT2B receptor
agonist, and MK 212, a selective 5-HT2C receptor
agonist, on the EPSP were examined. The amplitude of the EPSP was not
significantly increased by BW 723C86 (10 µM; 4 ± 2%; n = 4) or MK 212 (10 µM;
2 ± 2%; n = 4). Figure
4A shows the effects of
ketanserin (10 µM), a
5-HT2A/2C receptor antagonist, on the
facilitation of the EPSP induced by -methyl-5-HT (10 µM) in a DLSN neuron. In the absence of
ketanserin, the averaged amplitude of 30 EPSPs was increased from
6.4 ± 0.2 to 8.9 ± 0.4 mV by -methyl-5-HT. In the
presence of 10 µM ketanserin, the average
amplitude of 30 EPSPs was 6.5 ± 0.4 mV for control and 7.0 ± 0.3 mV for -methyl-5-HT (10 µM) (Fig.
4A). The pooled data showed that -methyl-5-HT (10 µM) produced only a 1.4 ± 1.1% (n = 7) increase in the amplitude of the EPSPs in
neurons treated with ketanserin (10 µM) (Fig.
4B). 5-HT (10 µM) also
produced only a 3.7 ± 2.8% (n = 6) increase in
the EPSP amplitude in the presence of ketanserin (10 µM) (Fig. 4B). The effect of
N-desmethylclozapine, a selective antagonist for
5-HT2C receptors, on the 5-HT-induced facilitation of the EPSP was also examined in DLSN neurons. In the
presence of N-desmethylclozapine (10 µM), -methyl-5-HT (10 µM) produced a 39 ± 6%
(n = 5) increase in the amplitudes of EPSPs (data not
shown). These results suggest that 5-HT2A
receptors are responsible for the 5-HT-induced facilitation of the EPSP in DLSN neurons. The effect of 8-OH-DPAT, an agonist for
5-HT1A and 5-HT7 receptors,
on the EPSP was examined, because the activation of
5-HT1A receptors mediates a hyperpolarizing
response in DLSN neurons (Joëls and Gallagher, 1988; Akasu et
al., 2000). When the (±)-8-OH-DPAT-induced hyperpolarization was
nullified by injection of depolarizing DC current, 8-OH-DPAT (10 µM) produced 21 ± 6% depression of the
EPSP in 5 of 12 cells. However, in the remaining 7 neurons, 8-OH-DPAT
(10 µM) did not change (6 ± 3%) the
amplitude of the EPSP. WAY 100135 (10 µM), a
selective 5-HT1A receptor antagonist, blocked the
8-OH-DPAT-induced depression of the EPSP (n = 3). We
examined the effects of 5-HT on the membrane potential of DLSN neurons
and the EPSP in the presence of WAY 100635, another selective 5-HT1A receptor antagonist. 5-HT (10 µM) did not produce a hyperpolarizing response
but produced a 52 ± 5% (n = 6) increase in the
amplitude of the EPSP in the presence of WAY 100635 (10 µM). CP 93129 (10 µM),
a 5-HT1B receptor agonist, SR 57227A (20 µM), a 5-HT3 agonist, RS
67506 (10 µM), a 5-HT4
receptor agonist, and 5-CT (2 µM), a 5-HT1,5 and 5-HT7 receptor
agonist, produced no significant change in the amplitude of the EPSP in
DLSN neurons (n = 4 for each experiment).
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Figure 4.
Effect of ketanserin (10 µM) on the
facilitation of the EPSP induced by -methyl-5-HT (10 µM). A, Effects of -methyl-5-HT (10 µM) on the EPSP examined in the absence and presence of
ketanserin (10 µM) in a DLSN neuron. Data points are
averages of six responses. The period of drug application is indicated
by horizontal bars. Bottom traces are
sample records of neuron responses at the time indicated by the
corresponding letters on the graph.
Open triangles indicate the time of fimbria stimulation.
B, Pooled data for the facilitation of the EPSP induced
by -methyl-5-HT (10 µM; open columns)
and 5-HT (10 µM; hatched columns) in the
absence and presence of ketanserin (10 µM). The number of
experiments is shown in parentheses. Error bars indicate
SEM. Ordinate, Percentage facilitation of the EPSP
amplitude. *Statistical significance (p < 0.01).
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We examined whether the facilitation of the EPSP by 5-HT is
attributable to increased sensitivity of receptors at the postsynaptic membrane. DLSN neurons were superfused with ACSF containing TTX (1 µM). Under the voltage-clamp condition,
L-glutamate was applied to the recorded neurons by pressure
pulses from a broken tip glass pipette containing
L-glutamate. Pressure application of glutamate to DLSN
neurons produced an inward current associated with an increase in the
membrane conductance. Pooled data showed that the amplitudes of the
exogenous glutamate-induced current were 346 ± 40 pA
(n = 5) and 338 ± 37 pA (n = 5)
in the absence and presence of 5-HT (10 µM),
respectively. The difference between these data is not statistically
significant. These results suggest that the 5-HT-induced enhancement of
the EPSP is not attributable to the increase in the glutamate response
at the postsynaptic membrane.
Effect of 5-HT on the mEPSCs
The evidence that an agonist can increase the frequency of mEPSPs
without changing their amplitudes suggests presynaptic facilitation of
excitatory synaptic transmission (Katz, 1969; Thompson et al., 1993).
Figure 5 shows the effects of
-methyl-5-HT on the frequency and amplitude of mEPSPs in DLSN
neurons. In this experiment, WAY 100135 (5 µM) and TTX (1 µM) were routinely applied to the external solution to
block the 5-HT-induced hyperpolarization and action potential,
respectively. The amplitude and frequency of mEPSPs were not
significantly affected by these two blockers. Figure 5A
shows amplitude histograms of the mEPSPs taken before and 10 min after
application of -methyl-5-HT (10 µM).
-Methyl-5-HT (10 µM) increased the number of
mEPSPs. The cumulative amplitude distribution of mEPSPs was plotted in
the absence or presence of -methyl-5-HT (10 µM`)
(Fig. 5B). -Methyl-5-HT (10 µM)
did not change the mean amplitude of the mEPSPs: 0.58 ± 0.07 mV
(n = 5) for control and 0.56 ± 0.06 (n = 5) mV for -methyl-5-HT (10 µM). -Methyl-5-HT had no effect on the time
course of the mEPSP, as shown by the traces of digitally averaged
mEPSPs (Fig. 5B, traces a, b). The cumulative
probability distribution of interevent intervals was plotted in the
absence and presence of -methyl-5-HT (10 µM)
(Fig. 5C). -Methyl-5-HT (10 µM) caused a shift in the interevent interval
distribution toward shorter intervals, indicating higher
frequencies. The mean frequency of mEPSPs was increased from 0.38 to
0.62 Hz in the presence of -methyl-5-HT (10 µM). Pooled data showed that -methyl-5-HT
(10 µM) produced a 72 ± 15%
(n = 5) increase in the frequency of the mEPSP. The
effect of 5-HT on the mEPSP was also examined in DLSN neurons. 5-HT
significantly increased the number of mEPSPs. The mean peak amplitude
was not affected (control, 0.62 ± 0.05 mV; 5-HT, 0.56 ± 0.08 mV) in five neurons. In these five neurons treated with 5-HT,
the frequency of mEPSPs increased from 0.27 ± 0.04 to
0.51 ± 0.1 Hz (p < 0.05). The
5-HT-induced increase in the frequency of mEPSP was 90 ± 19% (n = 5). These results suggest that 5-HT
enhances the spontaneous release of glutamate.
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Figure 5.
Effect of -methyl-5-HT on the mEPSP.
mEPSPs were recorded in the presence of TTX (1 µM) and
WAY 100135 (5 µM). The resting membrane potential was
-68 mV. A, Amplitude histogram of mEPSPs recorded
before (open columns) and during (hatched
columns) application of -methyl-5-HT. B,
Cumulative probability distribution of peak amplitudes of mEPSP before
and during application of -methyl-5-HT (10 µM) in the
same neuron as in A. Traces
a and b show the averaged mEPSP (65 events each) obtained before and during application of -methyl-5-HT
(10 µM), respectively. C, Cumulative
probability distribution of interevent intervals of mEPSPs before and
during application of -methyl-5-HT (10 µM) in the same
neuron as in A. The interevent interval was decreased,
but the amplitude distribution was unaffected by -methyl-5-HT.
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Effect of 5-HT on paired pulse facilitation of the EPSP
When the fimbrial pathway was stimulated by two consecutive
pulses, paired pulse facilitation of the EPSP was recorded in DLSN
neurons treated with bicuculline (15 µM) and CGP 55845 (4 µM) (Hasuo and Akasu, 2001). If a neurotransmitter (or
agonist) facilitates the release probability, the paired pulse ratio
would decrease (Manabe et al., 1993; Debanne et al., 1996). We measured the peak amplitude of the EPSPs evoked by a pair of pulses with an
interstimulus interval of 50 or 100 msec and calculated the amplitude
ratio of the second to the first EPSP in each pair. Figure
6 shows an example of these experiments.
In the absence of 5-HT, the averaged amplitude ratio of the second to
the first EPSP was 1.2, indicating paired pulse facilitation. When 5-HT (10 µM) was applied to the external solution, both the
first and second EPSPs in the pair increased their amplitudes. However, the facilitation of the first EPSP was greater than that of the second,
decreasing the paired pulse ratio to 1.0 in this neuron (Fig.
6A). Figure 6B shows the effect of
-methyl-5-HT on the paired pulse facilitation in a DLSN neuron.
-Methyl-5-HT (10 µM) increased the amplitude
of both the first and second EPSPs in the pair and decreased the pair
pulse ratio from 1.2 to 1.0. Figure 6C shows pooled data for
the depression of the paired pulse ratio induced by -methyl-5-HT. In
these experiments, -methyl-5-HT (10 µM)
depressed the paired pulse ratio to 85 ± 1% (n = 5) of control. These data suggest that 5-HT increases the probability of glutamate release from a readily releasable pool in presynaptic nerve terminals.
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Figure 6.
Effects on paired pulse facilitation of the EPSP.
A, Effects of 5-HT on the EPSP produced by paired pulse
stimulation (100 msec interpulse interval) in a DLSN neuron. The ACSF
contained bicuculline (15 µM) and CGP 55845 (4 µM). Two consecutive EPSPs were evoked in the absence
(a) and presence (b) of
5-HT (10 µM). B, Effect of -methyl-5-HT
(10 µM) on EPSPs evoked by paired pulse stimulation with
an interpulse interval of 50 msec in a DLSN neuron. Records
a and b were taken before and 5 min after
application of -methyl-5-HT (10 µM). In
A and B, sample traces
represent the digital average of six events. C, Pooled
data from five neurons for the effects of -methyl-5-HT (10 µM) on the paired pulse facilitation of the EPSP. Data
points represent the paired pulse ratios obtained in the absence
(left) and presence (right) of
-methyl-5-HT (10 µM). Columns show the
mean ± SEM for the depression of the paired pulse ratio in the
presence of -methyl-5-HT (10 µM; right
column). The paired pulse ratio obtained before application of
-methyl-5-HT (left column) was taken as 100%.
|
|
Protein kinase C mediates the 5-HT-induced facilitation of
the EPSP
We examined the contribution of protein kinases to the
5-HT-induced facilitation of the EPSP in the DLSN. Figure
7A shows the effect of 5-HT on
the EPSP examined before and during the application of calphostin C, a
specific inhibitor for PKC (Kobayashi et al., 1989). In this particular
cell, 5-HT increased the averaged amplitude of 30 EPSPs from 4.5 ± 0.6 to 7.0 ± 0.4 mV. During the application of calphostin C
(100 nM), the facilitation of the EPSP induced by
5-HT decreased with time. Application of calphostin C (100 nM) for 20 min completely abolished the
5-HT-induced facilitation of the EPSP. Pooled data showed that 5-HT (10 µM) produced only a 3 ± 1%
(n = 7) increase in the EPSP amplitude in neurons
treated with calphostin C (100 nM) for 30 min
(Fig. 7A). These data suggest that PKC plays a role in the
5-HT-induced facilitation of the EPSP in DLSN neurons. We also examined
a possible contribution of protein kinase A (PKA) to the 5-HT-induced
potentiation of the EPSP, because db-cAMP (1 mM)
and forskolin (10 µM) produced 90 ± 13%
(n = 6) and 132 ± 25% (n = 6)
increases, respectively, in the amplitudes of EPSPs. However, in the
presence of H-89 (10 µM), a membrane-permeable
and selective inhibitor of PKA (Chijiwa et al., 1990), 5-HT (10 µM) produced a typical facilitation (36 ± 8%; n = 5) of the amplitude of the EPSP (Fig.
7B). At a concentration of 10 µM,
H-89 suppressed the facilitation of the EPSP produced by application of
forskolin for 10 min (n = 3; data not shown). Therefore, a db-cAMP-dependent process may not be involved in the
5-HT-induced facilitation of the EPSP in DLSN neurons.
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Figure 7.
Effects of protein kinase inhibitors on the
5-HT-induced facilitation of the EPSP. A, Effect of 5-HT
on the EPSP before and after application of calphostin C (100 nM). Data points are averages of six responses. The period
of drug application is indicated by horizontal bars.
Bottom traces show sample records of neuron responses at
the times indicated by the corresponding letters on the
graph. Open triangles indicate the time
of fimbria stimulation. B, Pooled data for the
5-HT-induced facilitation of the EPSP. Open and
hatched columns show the presence of calphostin C and
H-89, respectively. The amplitude of the EPSP recorded before
application of 5-HT is taken as 100%. The number of experiments is
shown in parentheses. Error bars indicate SEM.
n.s., Difference has no statistical significance.
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|
The effect of PDBu, an activator of PKC, on the EPSP was examined in
DLSN neurons. Bath application of PDBu (3 µM) produced a
127 ± 30% (n = 5) increase in the amplitude of
the EPSP (Fig. 8A).
Figure 8B shows the effect of PDBu on the paired
pulse facilitation of the EPSP recorded from a DLSN neuron treated with
bicuculline (15 µM) and CGP 55845 (4 µM). Application of PDBu (3 µM) to the ACSF for 10 min clearly increased
the amplitude of both first and second EPSPs. The facilitation of the
first EPSP was greater than that of the second. Thus, paired pulse
facilitation was changed to paired pulse depression by PDBu in this
particular neuron (Fig. 8B). Pooled data showed that
PDBu (3 µM) depressed the paired pulse ratio
from 1.16 ± 0.04% (n = 3) to 0.80 ± 0.07%
(n = 3). We also examined the effect of PDBu on the
mEPSPs. Figure 8C shows the cumulative amplitude
distribution of mEPSPs obtained in the absence and presence of PDBu.
The mean amplitudes of the mEPSCs were 0.52 ± 0.03 mV
(n = 4) for control and 0.49 ± 0.04 mV
(n = 4) for PDBu (3 µM). Thus,
PDBu (3 µM) produced no significant change in
the amplitude distribution (p > 0.2). PDBu had
no effect on the time course of the mEPSP as shown by the traces of
digitally averaged mEPSPs in Figure 8C, traces a
and b. The cumulative interevent interval probability
distributions were plotted in the absence and presence of PDBu (3 µM) (Fig. 8D). PDBu (3 µM) caused a shift of the interevent interval
distribution toward shorter intervals, indicating higher frequencies.
The mean frequency of mEPSPs increased from 0.30 ± 0.03 Hz
(n = 4) to 1.65 ± 0.24 Hz (n = 4)
in the presence of PDBu (3 µM). These results
indicate that PDBu increases glutamate release from presynaptic nerve
terminals.
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Figure 8.
PDBu (3 µM) increases
excitatory synaptic transmission in DLSN neurons. A,
Effect of PDBu (3 µM) on the evoked EPSP in a DLSN
neurons. Left and middle traces were
obtained before and 15 min after bath application of PDBu. The
right trace was taken 100 min after withdrawal of PDBu.
B, Effect of PDBu (3 µM) on the paired
pulse facilitation of the EPSP. Left and right
traces were obtained before and 10 min after bath application
of PDBu. C, Cumulative amplitude distribution of mEPSPs
recorded before and during application of PDBu (3 µM).
mEPSPs were recorded in the presence of TTX (1 µM) and
bicuculline (15 µM). Traces a and
b show the mEPSP shape before and during application of
PDBu. D, Cumulative probability distribution of
interevent intervals of mEPSC in control and during application of PDBu
in the same neuron (as A). The interevent interval was
decreased, but the amplitude distribution was unaffected by PDBu.
|
|
Molecular cloning has established that all 5-HT receptor subtypes,
except 5-HT3 receptors, couple to the
G-protein-coupled receptor (Hoyer et al., 1994). It has been reported
that NEM, a membrane-permeable inhibitor for PTX-sensitive G-proteins
(Nakajima et al., 1990; Shapiro et al., 1994), irreversibly blocks the
5-HT-induced hyperpolarization (and current) in DLSN neurons (Yamada et
al., 2001). In the present study, we examined the effect of NEM on the
facilitation of the EPSP induced by 5-HT in DLSN neurons (Fig. 9). In the control ACSF, 5-HT (10 µM) caused a hyperpolarization in DLSN neurons and
enhanced the EPSP amplitude (Fig. 9A, a,
B, a). Application of NEM (200 µM) for >30 min markedly increased the
spontaneous EPSPs and strongly depressed the hyperpolarization induced
by 5-HT (10 µM) (Fig. 9A,
b). At the same time, 5-HT (10 µM),
however, produced a typical facilitation (44 ± 10%;
n = 4) of the EPSP (Fig. 9B, b).
It has been reported that baclofen, a GABAB
receptor agonist, presynaptically depresses the EPSC in DLSN neurons
(Yamada et al., 1999), and that the presynaptic
GABAB receptors on glutamatergic nerve terminals
couple to NEM-sensitive G-protein in rat auditory brainstem (Isaacson,
1998). We examined the effect of baclofen on the EPSP in neurons
treated with NEM to test whether the presynaptic G-protein is indeed
sensitive to NEM. Figure 9C shows that baclofen depressed
the EPSP in the absence of NEM. In the same cell, NEM (200 µM) was then applied for >20 min. Baclofen (5 µM) produced no obvious suppression of the EPSP
in neurons that had been treated with NEM. The results suggest that NEM
blocks presynaptic PTX-sensitive G-protein in the DLSN.
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Figure 9.
Effects of NEM on the 5-HT-induced facilitation of
the EPSP. A, Effects of NEM (200 µM) on
the 5-HT-induced hyperpolarization. Records a and
b were taken before and 30 min after application of NEM
(200 µM). Solid horizontal bars indicate
the period of bath application of 5-HT (10 µM).
B, Effects of 5-HT (10 µM) on the EPSP in
a DLSN neuron before and 30 min after application of NEM (200 µM). Top and bottom traces
in a and b were taken before and 5 min
after application of 5-HT, respectively. Note that 5-HT increased the
amplitude of the EPSP in the presence of NEM. C, Effects
of NEM (200 µM) on the baclofen-induced (5 µM) suppression of the EPSP. Records a and
b were taken before and 20 min after application of NEM
(200 µM).
|
|
| |
DISCUSSION |
Presynaptic facilitation by 5-HT
The present study characterized the facilitatory modulation of
excitatory synaptic transmission by exogenously applied 5-HT in brain
slices containing the dorsolateral septal nucleus. Under current-clamp
conditions, 5-HT increased the amplitude of the EPSP evoked in DLSN
neurons by stimulation of the fimbria. Under voltage-clamp conditions,
5-HT also increased the amplitude of the EPSC, indicating that the
facilitation of the EPSP is independent of the changes in the membrane
potential and conductance at the postsynaptic membrane. Previous
studies have shown that 5-HT strongly depresses both fast and slow
IPSPs in DLSN neurons (Joëls et al., 1987; Joëls and
Gallagher, 1988; Akasu et al., 2000). However, the facilitation of the
EPSP is not attributable to the inhibition of IPSPs, because 5-HT
directly facilitated the EPSP in the presence of bicuculline and CGP
55845, blockers for the fast and slow IPSPs, respectively, in DLSN
neurons. Because CGP 55845 not only blocks postsynaptic
GABAB receptors but also blocks presynaptic
GABAB receptors (Yamada et al., 1999), the
facilitatory action of 5-HT is not mediated by the presynaptic
GABAB receptors located on the glutamatergic
synapse. Multiple lines of evidence indicate a presynaptic facilitation
of the EPSP by 5-HT. First, 5-HT did not alter the response to
exogenously applied L-glutamate, suggesting that 5-HT does
not change the sensitivity of glutamate receptors at the postsynaptic
neurons. Second, 5-HT increased the frequency of mEPSPs without
changing their amplitude. Third, 5-HT depressed paired pulse
facilitation of the EPSP. These results suggest that 5-HT increases the
release probability of glutamate at presynaptic nerve terminals.
Receptor subtype and signal transduction mechanism
The subtype of 5-HT receptors mediating the presynaptic
facilitation of the EPSP was investigated in DLSN neurons.
5-HT1A receptors do not seem to mediate the
facilitation of the EPSP, because 8-OH-DPAT produced no facilitation
but a depression of the amplitude of the EPSP in a subpopulation of
DLSN neurons. In a majority of DLSN neurons, 8-OH-DPAT did not produce
a significant effect on the EPSP. 5-HT1A
receptor-mediated depression of the EPSP and EPSC has been shown in
hippocampal CA1 neurons (Schmitz et al., 1995) and dorsal
horn neurons of the spinal cord (Hori et al., 1996). We observed that
5-HT produced an ~52% increase in the EPSP amplitude in the presence
of WAY 100635, a selective 5-HT1A receptor
antagonist. 5-HT1B receptors have been shown to mediate the inhibition of the EPSP in several regions of the CNS (Bobker and Williams, 1989; Mooney et al., 1994; Singer et al., 1996;
Li and Bayliss, 1998; Hwang and Dun, 1999). However, CP 93129, a
selective 5-HT1B receptor agonist, did not affect
the amplitude of the EPSP. -Methyl-5-HT, a broad-spectrum
5-HT2 receptor agonist, increased the amplitude
of the EPSP. The 5-HT2B and
5-HT2C receptor agonists BW 723C86 and MK 212, respectively, produced no significant change in the
amplitude of the EPSP. Ketanserin, a 5-HT2A/2C
receptor antagonist, blocked the facilitation of the EPSP induced by
5-HT or -methyl-5-HT. In contrast, N-desmethylclozapine (10 µM), a 5-HT2C
receptor antagonist, did not antagonize the facilitation of the EPSP
induced by -methyl-5-HT (10 µM).
-Methyl-5-HT also mimicked the effects of 5-HT on mEPSPs and on the
paired pulse ratio of the EPSP. These results suggest that presynaptic 5-HT2A receptors are responsible for the
presynaptic facilitation of the glutamate release in the DLSN.
Previous studies have demonstrated that 5-HT stimulates phospholipase C
and phosphatidylinositol turnover through 5-HT2
receptors, resulting in the activation of PKC (Hoyer et al., 1994). The
present study showed that calphostin C, a selective PKC inhibitor,
depressed the 5-HT-induced facilitation of the EPSP. Application of
PDBu, an activator of PKC, produced a facilitation of the EPSP. PDBu also markedly increased the frequency of mEPSPs without changing their
amplitude. Paired pulse facilitation was markedly depressed by PDBu.
Although db-cAMP and forskolin increased the EPSP amplitude, H-89 did
not depress the 5-HT-induced facilitation of the EPSP. These results
suggest that PKC mediates the 5-HT-induced presynaptic facilitation of
the EPSP. The signal transduction process for the 5-HT-induced
facilitation of the glutamate release remains to be determined at
present. Pharmacological studies suggested the involvement of a PKC
pathway in the facilitatory action of 5-HT. A previous study also
showed that the presynaptic modulation produced by 5-HT via a PKC
pathway was characterized by slow onset and long duration in central
neurons (Byrne and Kandel, 1996; Hori et al., 1996). Recently, 5-HT has
been shown to enhance spontaneously occurring EPSP by modulating
voltage-dependent Na+ and
Ca2+ channels in neocortical layer V
pyramidal cells (Aghajanian and Marek, 1997). The present study showed,
however, that the 5-HT-induced increase in the frequency of the mEPSP
was seen in the presence of TTX. It has been shown that phorbol ester
itself facilitates transmitter release independently of the external
calcium concentration (Malenka et al., 1986; Murphy and Smith, 1987;
Shapira et al., 1987). Hori et al. (1999) have demonstrated that
phorbol ester causes a presynaptic facilitation of synaptic
transmission in the calyx of Held, a giant presynaptic
terminal in the rodent brainstem. They proposed that the target of the
presynaptic facilitatory effect of phorbol ester was located downstream
of the calcium influx and may involve a PKC and Doc2a-Munc13-1
interaction in the transmitter release process. A similar PKC-dependent
phosphorylation process might be involved in the 5-HT-induced
facilitation of the EPSP in DLSN neurons. Molecular cloning has
established that all 5-HT receptor subtypes, except
5-HT3 receptors, belong to the superfamily of the
G-protein-coupled receptors (Hoyer et al., 1994). It has been shown
that presynaptic GABAB receptors on glutamatergic nerve terminals couple to a G-protein that is sensitive to NEM, an
uncoupler of receptors from PTX-sensitive G-protein (Nakajima et al.,
1990; Shapiro et al., 1994). In the DLSN, activation of presynaptic
GABAB receptors inhibits the EPSC (Yamada et al., 1999). The present study showed that application of NEM blocked the
baclofen-induced depression of the EPSP. These results suggested that
NEM can block presynaptic G-protein that mediates the presynaptic inhibition of the EPSP in the DLSN. In contrast, 5-HT caused a typical
facilitation of the EPSP in DLSN neurons treated with NEM. We suggest
that the 5-HT2A receptor is coupled to a
PTX-insensitive G-protein, mostly the Gq/G11
class (Alexander et al., 2001), or directly activates PKC in DLSN neurons.
Physiological and pathophysiological roles of 5-HT
Under a current-clamp condition, 5-HT ceased spontaneous firing of
action potentials by producing hyperpolarization, and it facilitated
the excitatory synaptic transmission. This results in an enhancement of
the signal-to-noise ratio in DLSN neurons. The 5-HT-induced
facilitation of the excitatory synaptic transmission is long-lasting
even after washout of 5-HT, suggesting that 5-HT may contribute to the
plasticity of synaptic transmission, such as long-term potentiation. It
has been shown that the effect of 5-HT on synaptic transmission is
use-dependent (Montarole et al., 1986). We observed that repeated
application of 5-HT produced a facilitation of the EPSP in some DLSN
neurons but showed no significant facilitation of the EPSP during
antecedent 5-HT application.
The 5-HT2A receptor has been implicated in
numerous emotional disorders, including depression, anxiety, psychosis,
and schizophrenia (for review, see Naughton et al., 2000). It is
hypothesized that abnormal neurotransmission at
5-HT2 receptors is involved in the pathophysiology of schizophrenia (Laruelle et al., 1993). Typical antipsychotic drugs, such as clozapine, olanzapine, and risperidone, have a strong therapeutic effect on schizophrenia as a combination blockers for D1/D2 and
5-HT2A receptors (Leonard, 1997). As is the case
for the limbic system, the lateral septum is known to participate in a
variety of physiological and behavioral processes related to emotions,
such as aggressiveness, fear, and other socially and sexually related
behaviors (Lisciotto et al., 1990). The facilitation of excitatory
synaptic transmission between the hippocampus and the lateral septum
may be involved in 5-HT2A receptor-mediated improvement of emotional and mental disorders.
| |
FOOTNOTES |
Received Oct. 14, 2001; revised May 24, 2002; accepted May 5, 2002.
This work was supported in part by The Ishibashi Research Fund and a
grant-in-aid for Scientific Research (B) from the Ministry of
Education, Science, Sports, and Culture of Japan. We thank Dr. C. Polosa for reading this manuscript and for helpful comments.
Correspondence should be addressed to Dr. Hiroshi Hasuo, Department of
Physiology, Kurume University School of Medicine, 67 Asahi-machi,
Kurume 830-0011, Japan. E-mail: hhasuo{at}med.kurume-u.ac.jp.
| |
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ABSTRACT
INTRODUCTION
