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J Neurophysiol (November 1, 2002). 10.1152/jn.00352.2002
Submitted on 8 May 2002
Accepted on 24 July 2002
Department of Anatomy and Cell Biology in the Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, New York 10032
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Jo, Young-Hwan and
Lorna W. Role.
Cholinergic Modulation of Purinergic and
GABAergic Co-Transmission at In Vitro Hypothalamic Synapses.
J. Neurophysiol. 88: 2501-2508, 2002.
The lateral
hypothalamus (LH) is an important center for the integration of
autonomic and limbic information and is implicated in the modulation of
visceral motor and sensory pathways, including those underlying feeding
and arousal behaviors. LH neurons in vitro release both ATP and GABA.
The control of ATP and GABA co-transmission in LH may underlie the
participation of LH in basic aspects of arousal and reinforcement. LH
neurons receive cholinergic input from the pedunculopontine and
laterodorsal tegmental nuclei as well as from cholinergic interneurons
within the LH per se. This study presents evidence for nicotinic
acetylcholine receptor (nAChR)-mediated enhancement of GABAergic, but
not of purinergic, transmission despite the co-transmission of ATP and
GABA at LH synapses in vitro. Facilitation of GABAergic transmission by
nicotine is inhibited by antagonists of (
)*-containing nAChRs,
but is unaffected by an 7-selective antagonist, consistent with a
nAChR-mediated enhancement of GABA release mediated by
non-7-containing nAChRs. Activation of muscarinic ACh receptors
enhances the release of ATP while concomitantly depressing GABAergic
transmission. The independent modulation of ATP/GABAergic transmission
may provide a new level of synaptic flexibility in which individual
neurons utilize more than one neurotransmitter but retain independent
control over their synaptic activity.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The cholinergic systems in
the brain have been implicated in a variety of behavioral and cognitive
functions, such as working memory and aspects of learning, attention,
and arousal. Nicotine alters such cognitive and behavioral functions
through specific interactions with nicotinic acetylcholine receptors
(nAChRs) found within the diffuse terminals fields of central
cholinergic projections (Jones et al. 1999
; Levin
1992; Woolf 1991). Nicotine receptors are found
in cell bodies, dendrites, and at presynaptic sites in areas that
receive cholinergic projections. Recent electrophysiological studies
have provided direct evidence for nAChR-mediated synaptic transmission
at central synapses (Alkondon et al. 1998;
Frazier et al. 1998; Hefft et al. 1999;
Jones et al. 1999; Nong et al. 1999). In addition, nAChRs are targeted to synaptic
terminals and preterminal domains, consistent with demonstrated effects of ACh and nicotine on the release of a wide variety of
neurotransmitters (as reviewed in MacDermott et al.
1999).
Activation of pre- and/or postsynaptic nAChRs of GABAergic neurons has
been shown to modulate GABA release in several brain areas
(Alkondon et al. 2000; Guo et al. 1998;
Lena and Changeux 1997; Zhu and Chiappinelli
1999). Our previous study (Jo and Role 2002) and
other recent work have demonstrated the release of GABA with other
fast-acting neurotransmitters (Jo and Schlichter 1999; Jonas et al. 1998; Keller et al. 2001).
At GABA-glycine synapses, the neurotransmitters are packaged within the
same vesicles by the vesicular inhibitory amino acid transporter
(Gasnier 2000) and the release of both GABA and glycine
is modulated by presynaptic GABAB receptors
(Jonas et al. 1998). Thus it appears that the contribution of GABA and glycine to the inhibitory control of postsynaptic excitability is coordinately regulated.
The present study tested whether the co-transmission of ATP and
GABA in lateral hypothalamus (LH) (Jo and Role 2002) are
modulated by cholinergic agonists in general and whether the effects of cholinergic modulators differentially alter purinergic versus GABAergic
transmission in particular. The neurons of the lateral hypothalamic
area (LHA) are important for behavioral aspects of feeding and arousal
(Willie et al. 2001) and comprise an important target of
cholinergic neurons from the pedunculopontine and laterodorsal tegmental nuclei (Chemelli et al. 1999) as well as
within the LH (Tago et al. 1987). Reciprocal
interactions of the LHA with the cholinergic pedunculopontine and
laterodorsal tegmental nuclei may underlie the participation of LH in
feeding and reinforcement. Several subtypes of both nicotinic and
muscarinic AChRs (mAChRs) are expressed within the LH including 4-,
7-, 8-, and 2-type nAChRs and m1- and m2-type mAChRs
(Britto et al. 1992; Ehlert and Tran
1990; Okuda et al. 1993; Wei et al.
1994). We tested whether the coordinate release of ATP and GABA
was inextricably linked to coordinate modulation of transmission by
cholinergic agonists. These studies revealed that cholinergic
modulators exert independent control over GABA versus ATP transmission,
suggesting potential mechanisms whereby synapses that utilize more than
one neurotransmitter nevertheless retain the signaling flexibility afforded by differential, heterosynaptic modulation (MacDermott et al. 1999).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Neuronal cultures
Primary cultures of LH neurons were prepared from embryonic day
11 chick using the following protocols (also see Jo and Role 2002). The region of the hypothalamus was identified on the
ventral aspect of the brain with the exterior border delineated by the optic chiasm and the posterior border delineated by the infundibular stalk. The lateral-most portions of the demarcated area were excised, microdissected, and incubated at 37°C in divalent cation-free Earle's balanced salt solution (EBSS, Gibco) containing papain (20 U/ml, Sigma) and L-cysteine (1 mM, Sigma). After 20 min of incubation the tissue was mechanically dispersed by repeated passage through a heat-polished pasteur pipette. Papain activity was
neutralized by adding 10 ml EBSS containing bovine serum albumin (BSA,
1 mg/ml, Sigma) and the preparation was centrifuged for 5 min at
300g. The preparation for plating was collected by removing
the supernatant and resuspending the pelleted neurons in complete
medium composed of DMEM (Gibco), heat-inactivated horse serum (10%
v/v, Gibco), chick extract (10% v/v, house-made), penicillin and
streptomycin (50 IU/ml for each, Gibco), and NGF (10 nM). LH neuron
preparations obtained from approximately 12 E11 chick hypothalami were
plated on six 35-mm poly-L-ornithine-coated
tissue culture plastic dishes. The culture media were replaced once
each week and LH neurons were maintained until use in a water-saturated
atmosphere (95% O2-5%
CO2) at 37°C.
Electrophysiological recording
Electrophysiological recordings were conducted between 7 and 15 days after plating. Membrane currents were recorded at room temperature
(20-22°C) with an Axopatch 200B amplifier (Axon Instruments) in the
perforated patch-clamp configuration using amphotericin B. The external
solution contained (in mM) 135 NaCl, 5 KCl, 2.5 CaCl
2, 1 MgCl 2, 5 HEPES, and
10 glucose, pH 7.3. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)
(10 µM) and DL-amino-phosphonovaleric acid
(DL-AP-5, 50 µM) were continuously present in the
external solution. The amphotericin B (Sigma) stock solution (30 mg/ml)
was prepared in DMSO just before the recording session. The pipette was
first filled at the tip with internal solution containing (in mM) 70 Cs
2SO 4, 9 CsCl, and 10 HEPES, pH 7.3, and then was back-filled with the same solution
containing amphotericin B (150 µg/ml). Under these conditions, the
equilibrium potential for Cl
ions
(ECl) was approximately 
70 mV.
Adjustment of the equilibrium potential for Cl
ions (ECl) to 70 mV and
Ecations to 0 mV allowed recording of cation-mediated components of synaptic transmission at a holding potential (VH) of 70 mV and
Cl ions-mediated component at a
VH of 0 mV.
Eliciting evoked postsynaptic currents (PSCs) and detection of miniature PSCs (mPSCs)
For extracellular stimulations, a double-barreled electrode
(World Precision Instruments), filled with extracellular solution, was
placed in contact with the cell body of a potential presynaptic partner
of the recorded neuron. Stimulation was performed with short single or
pairs of stimuli [interval: 300 ms for GABAergic evoked inhibitory
postsynaptic currents (eIPSCs) and 150 ms for purinergic evoked
excitatory postsynaptic currents (eEPSCs); 0.1 ms, 20 and 100
µA] delivered at 0.1 Hz. Our typical protocol for isolation of
purinergic evoked PSCs involved setting ECl to -70 mV (as described above) and recording at a
VH of -70 mV in the continuous
presence of CNQX, DL-AP5, strychnine, and bicuculline (abbreviated as CABS). GABAergic IPSCs were detected by setting ECl to -70 mV and recording at a
VH of 0 mV in the continuous presence
of CNQX, DL-AP-5, strychnine (10, 50, and 1 µM; referred to as CAS) but without bicuculline. Individual, spontaneously occurring
mPSCs were analyzed off-line using commercially available software
(Mini analysis 5.0 from Synaptosoft or Axograph 4.0 from Axon
Instruments). For each experiment, the threshold for detection was set
>5 pA (approximately 2 times the peak-to-peak noise). Recordings were
also visually inspected to verify the detection of small amplitude
events. For analysis of the decay phase of mPSCs, the events were
selected on the basis of the following criteria: 1) stable
baseline recording both before the rise and after the end of mPSC,
2) single events detected with a minimum interval of >100
ms between events, and 3) rise times (10-90% of the peak
amplitude of the mPSCs) of acceptable events were <3 ms. For
examination of average mPSCs profiles, the events were aligned by their
initial rising phase. Voltage and current traces were stored on a
videotape recorder and/or the hard drive of the analysis computer after
being filtered at 5 kHz by Axopatch 200B. Acquisition and analysis were
performed using pClamp6, Axograph 4.0 (Axon Instruments) and Mini
analysis 5.0 (Synaptosoft). Student's t-tests were used to
analyze the difference between parameters. The critical value for
statistical significance was set at P < 0.05. All
statistical results are given as mean ± SE.
Preparation and application of drugs and other reagents
Most reagents were prepared as 1,000× concentrated stock solutions. Bicuculline methiodide, strychnine, TTX, muscarine chloride, and nicotine hydrogen tartrate salt were obtained from Sigma (St. Louis, MO), prepared in distilled water, aliquoted and stored at -20°C. DL-APV (Sigma) was prepared in 100 mM NaOH solution and CNQX (Tocris) in 100% DMSO. The substances to be tested were diluted 1,000× to the final concentrations in extracellular solution immediately prior to the recording session and bath applied at a flow rate of 2-3 ml/min.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cholinergic modulation by nicotinic AChRs: differential effects on GABA versus ATP transmission
To examine how cholinergic activation might modulate synaptic
transmission between LH neurons, we first tested the effects of
nicotine on spontaneous (i.e., TTX-resistant) mPSCs mediated by the
activation of ATP P2X and GABAA receptors.
Nicotine (500 nM) increases the frequency of miniature GABAergic IPSCs
(mIPSCs) more than twofold (range 144 to 293%; 212 ± 27% versus
untreated control; n = 5 cells; Fig.
1, A and B).
Despite such robust increases in GABAergic mIPSCs frequency, neither
the amplitude (Fig. 1, C and D) nor the decay
kinetics of mIPSCs were affected (control: decay 
= 49 ± 2 ms; mIPSC + nicotine = 49 ± 3 ms; n = 5). Such findings are consistent with presynaptic effects of nicotine
on GABA release.
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The presynaptic modulation of GABAergic transmission is further
supported in experiments demonstrating nicotine-induced facilitation of
evoked IPSCs (eIPSCs). Brief exposure (1 min) of identified synaptic
pairs to nicotine (0.5 µM) induced a reversible facilitation of
eIPSCs (Fig. 2, A1 and
C). With paired pulse stimulation, nicotine significantly
increased the amplitude of evoked IPSCs, enhancing the first IPSC
(I1) more than the second
(I2); (Fig. 2, A and B; the
percent increase in the amplitude of I1 was
158.6 ± 12% of control; n = 10). Thus nicotine
enhanced both the average IPSC and the extent of paired pulse
depression (the paired pulse depression ratio is defined as
[(I1 I2) × 100]/I1; control: 13.9 ± 3.2%, nicotine:
29.7 ± 7.4%; n = 8; P < 0.05;
Fig. 2B). The decay time constant of eIPSCs is not
significantly affected by nicotine (control: fast: 20.8 ± 2, slow: 126.7 ± 11; nicotine:
fast: 19.8 ± 2.7, slow: 119 ± 12; n = 9;
P > 0.05). Facilitation of GABAergic transmission by
nicotine was inhibited by antagonists of ()* nAChRs, such as
mecamylamine (1 µM), but was unaffected by the (7)* nAChRs antagonist methyllycaconitine (10 nM; data not shown). The observed effects of nicotine on mIPSCs as well as on evoked GABAergic
transmission are consistent with a nicotinic AChR-mediated enhancement
of GABA release involving non-7-containing nAChRs.
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We next tested for nicotinic AChR-mediated changes in purinergic
transmission, expecting that the release of ATP, like GABA, would be
enhanced by nicotine. Contrary to our expectation, we found that
neither evoked nor spontaneous (TTX-resistant) purinergic transmission
was significantly affected by activation of nicotinic AChRs.
Application of nicotine (500 nM) at the same synapses where we had
observed nicotine-enhanced GABAergic spontaneous transmission revealed
no change in the frequency of miniature purinergic EPSCs (Fig.
3, A and B; see
also Fig. 1). In five neurons receiving both GABA and ATP input,
nicotine (500 nM) increased the frequency of miniature GABAergic IPSCs
(mIPSCs) more than twofold, whereas the frequency of ATP
P2XR-mediated mEPSCs remained equivalent to control (104 ± 9% + nicotine versus control). Nicotine changed neither the mean amplitude
nor the distribution of amplitudes of the mEPSCs (mean amplitude;
control: 11 ± 1 pA, nicotine: 11.3 ± 0.8 pA;
n = 5 cells; Fig. 3, C and D).
Nicotine was also without effect on the decay time constants of ATP
receptor-mediated mEPSCs (decay; control: 15.9 ± 2 ms, nicotine:
16.4 ± 3 ms; n = 5 cells; Fig. 3D).
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To test whether nicotine alters evoked transmission mediated via ATP P2X receptors, we examined purinergic excitatory postsynaptic currents evoked by suprathreshold stimulation of presynaptic inputs (eEPSCs) before and after nicotine treatment. The amplitude of purinergic eEPSCs was unaffected by application of nicotine (500 nM; Fig. 3, E1 and G). The mean change of amplitude was 105.3 ± 0.1% of control (n = 7 cells). The paired-pulse depression (PPD) and the decay time constant of purinergic eEPSCs were also unaffected by the activation of nAChRs (control: 39.2 ± 5%, nicotine: 34 ± 7%; n = 7 cells; Fig. 3, E2 and F). Thus, despite the co-transmission of ATP and GABA, signaling via these pathways appears to be differentially affected by the activation of presynaptic nAChRs in LH.
Cholinergic modulation of GABA and ATP transmission by muscarinic receptor activation
As endogenous ACh, unlike nicotine, activates muscarinic as well as nicotinic AChRs, we also tested the effects of mAChR activation on GABA and ATP co- transmission in LH. Such studies revealed that activation of mAChRs at LH synapses modulates both GABAergic and purinergic transmission. In addition, we found that the effects of muscarinic receptor activation contrast with those elicited by nicotine.
Activation of muscarinic receptors depressed both spontaneous and evoked GABA release. The frequency of GABAergic mIPSCs was decreased by 45.4 ± 5% of control levels (Fig. 4, A and B; range 28 to 62; n = 8), although neither the amplitude distributions nor the decay time constants of the GABAergic mIPSCs were altered (Fig. 4, C and D; mean amplitude; control: 12.6 ± 1 pA, muscarine: 11.8 ± 1 pA; n = 8; P > 0.05; decay; control: 53.7 ± 3.3 ms, muscarine: 51.6 ± 2.6 ms; n = 8; P > 0.05). Consistent with the depression of spontaneous GABAergic transmission, the average amplitude of eIPSCs was also decreased (20 ± 2% compared with control) and the PPD ratio was diminished from 27 ± 3% under control conditions to 11 ± 3% by mAChR activation (n = 6; P < 0.05; Fig. 5, A and B). Thus muscarinic AChR activation elicits an overall depression of GABAergic transmission in the LH.
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In contrast to the observed depression of GABAergic transmission by
mAChR activation, cholinergic activation of muscarinic receptors
enhanced purinergic transmission. The frequency of P2X receptor-mediated mEPSCs is increased by the activation of mAChRs. The
mean percent enhancement of purinergic mEPSCs was 163 ± 8% of
control (n = 5 cells; Fig.
6). Muscarine was without effect on
either the amplitude distribution or the decay time constant of
purinergic mEPSCs, consistent with an enhancement of ATP release rather
than a change in postsynaptic ATP sensitivity (Fig. 6, C and
D; mean amplitude, control: 10.9 ± 1.4 pA;
muscarine: 11 ± 0.9 pA; control: 12.4 ± 1.5 ms,
muscarine: 12.3 ± 1.5 ms; n = 5 cells;
P > 0.05). The activation of mAChRs increased the
amplitude of stimulus-evoked ATP P2XR-mediated eEPSCs (Fig.
7). The mean percent enhancement of
purinergic eEPSCs was 128 ± 17% of control (n = 4 cells). The PPD ratio was also significantly enhanced, increasing
from 24 ± 9% in control to 36.5 ± 7% with muscarine treatment (n = 4; P < 0.05; Fig. 7,
A2 and B).
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The net effects of cholinergic activation on GABAergic and purinergic transmission in the LH are compared and contrasted in Fig. 8. Cholinergic modulation of LH synapses via nicotinic pathways elicits significant facilitation of GABAergic transmission, without affecting purinergic transmission at ATP/GABA synapses. In contrast, activation of cholinergic pathways via muscarine enhances both spontaneous and evoked purinergic synaptic transmission and depresses GABAergic transmission at the same synapses.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our study demonstrates that GABAergic and purinergic transmission in the LH are differently and oppositely modulated by agonists of both ionotropic and metabotropic ACh receptors. Thus, despite the co-transmission by GABAA and ATP P2X-Rs-mediated synapses, purinergic and GABAergic transmission can be modulated independently from one another, depending on the nature of the cholinergic receptor-mediated pathway involved.
Several findings are consistent with a prominent role of presynaptic nicotinic and muscarinic receptors in the modulation of GABA/ATP transmission. First, the observed changes in "mini" frequency were not accompanied by changes in either the amplitude distribution or the decay time constants of spontaneous events mediated by GABAergic or purinergic transmission. Second, the PPD ratio of both GABAergic and purinergic evoked PSCs was significantly affected. In addition, nicotine was without effect on the macroscopic current responses elicited by exogenous application of GABA under the same experimental conditions as the synaptic transmission measurements. Thus the data are consistent with a presynaptic mechanism of cholinergic modulation.
The independent modulation of ATP and GABA transmission in conjunction
with the co-transmission of ATP and GABA in LH, as previously
demonstrated (Jo and Role 2002), could be explained by
several different mechanisms. For example, the positive modulation of
GABA release in the absence of a nicotinic effect on purinergic transmission may be due to a low probability of ATP release at ATP-GABA synapses. In this scenario, the activation of nAChRs would
not be sufficient to elicit an enhancement of ATP release. To test this
possibility, we examined the effect of nicotine on purinergic mEPSCs
under the conditions in which both
[K+]ext and
[Ca2+]ext were increased
from 5 to 10 and from 2.5 to 5 mM, respectively, to increase the
probability of neurotransmitter release. Even under these conditions of
elevated purinergic transmission, nicotine was without effect on the
frequency of ATP P2XR-mediated mEPSC (data not shown). As such, it
seems unlikely that the probability of ATP release per se underlies the
differential modulation of GABA versus ATP transmission by nicotine.
Perhaps the simplest model for the differential modulation of ATP and GABA transmission involves the segregation of presynaptic nicotinic and muscarinic receptors combined with functionally separate pools of ATP- versus GABA-containing vesicles. Alternatively there could be the segregation of both pre- and postsynaptic receptors, with storage of ATP and GABA within the same vesicular pool. Both models require selective targeting and/or spatial segregation of nicotinic and muscarinic receptors to distinct presynaptic domains to explain the observed differential modulation of ATP versus GABA transmission by cholinergic agonists.
Arguments consistent with the model that emphasizes independent storage
of ATP and GABA in distinct synaptic vesicles include prior support for
separate storage of ATP versus NE, despite their coordinate release
from peripheral sympathetic nerve of guinea pig vas deferens
(von Kugelgen and Starke 1991). Other reports consistent
with co-transmission, but separate storage of ATP and norepinephrine in
peripheral neurons, describe differential effects of prejunctional
-adrenoceptors (Goncalves et al. 1996) and
prostaglandin E 2 receptor activation
(Trachte et al. 1989). A variation on the former model
is raised by recent work of Lester and colleagues (Khakh et al.
2000) showing that the gating of P2X 2-
type receptors can inactivate nearby nAChRs. Such inhibitory
interactions between presynaptic P2X and nAChRs may underlie the
differential modulation of ATP versus GABA transmission by nicotinic
agonists per se.
The alternative model proposing storage of ATP and GABA within the same
vesicle population of individual LH neurons is clearly quite novel and
more complex. Here, independent modulation of transmission relies on
the targeting of cholinergic receptors to presynaptic domains
specifically apposed either to postsynaptic sites with both GABA and
ATP receptors or to postsynaptic sites with GABA receptors, but devoid
of ATP receptors. The concept of selective pre- and postsynaptic
receptor targeting has been suggested by other work. Previous studies
of rat sensory cortical neurons propose that nicotine acts at
presynaptic sites, selectively enhancing glutamate release only at
sites that include postsynaptic N-methyl-D-aspartate-type glutamate
receptors (Aramakis and Metherate 1998). The possibility
of co-localization of ATP P2X and GABAA receptors
is raised by our previous studies of the modulation of mPSCs kinetics
by flunitrazepam at GABA-ATP co-transmitting synapses (Jo and
Role 2002). Such a mechanism, based on the differential detection of transmitters at distinct postsynaptic domains of the same
neuron, is akin to models proposing that targeted expression of
specific receptor subtypes may underlie the plasticity of converting "silent" to "nonsilent" synapses (Gomperts et al.
1998). It is tempting to speculate that the detection of
released GABA versus ATP might be similarly subject to modification,
changing with development or with changes in synaptic activity.
Either configuration could account for modulation of ATP/GABA co-transmission in LH. Selective activation of nicotinic pathways associated with "GABAA receptor only" postsynaptic sites would elicit a net enhancement of inhibitory transmission (i.e., GABA > ATP transmission). Activation of cholinergic afferents sufficient to elicit muscarinic receptor-mediated pathways may result in a net disinhibition of synaptic transmission (i.e., ATP > GABA transmission).
Despite the extensive expression of P2X receptors in the hypothalamus,
previous work has not emphasized a physiological role for ATP-mediated
synaptic transmission in this region, in general, or in the lateral
hypothalamus, in particular. The primary physiological role for ATP
transmission suggested to date includes aspects of sensory
transduction, nociception, thermal hyperalgesia, and mechanical allodynia (Dunn et al. 2001; Khakh
2001). In contrast, GABA is the primary inhibitory
transmitter in the hypothalamus and glutamic acid decarboxylase mRNA is
widely expressed within the LH (Elias et al. 2001).
Recent studies demonstrate the existence of GABAergic interneuronal
synapses in in vitro preparations of rat lateral hypothalamus
(Gao and van den Pol 2001). Microinjection of the GABA
agonist, muscimol, into the LH depresses food intake (Grandison and Guidotti 1977) and the GABA antagonist, bicuculline, causes an increase in food intake when injected into the LH (reviewed in
Bernardis and Bellinger 1996). Several studies support a
potentially important role of LH inhibitory circuits in the central
control of feeding (for review see Bernardis and Bellinger
1996).
Our prior study (Jo and Role 2002) revealed ATP P2X
receptor-mediated transmission in both avian and rodent LH in vitro. In this report, we have extended our analysis of purinergic and GABAergic co-transmission in the LH to assess the potential modulatory role of
nicotinic and muscarinic cholinergic agonists. The independent modulation of released ATP and GABA observed at LH synapses in vitro
may provide a new level of synaptic flexibility in which individual
neurons utilize more than one neurotransmitter but retain independent
control over their synaptic activity. Selective facilitation of
GABAergic transmission by nicotinic pathways would elicit a net
enhancement of inhibitory transmission (i.e., GABA > ATP
transmission). Activation of cholinergic afferents sufficient to elicit
muscarinic receptor-mediated pathways may result in a net disinhibition
of synaptic transmission (i.e., ATP > GABA transmission). The
current findings support the notion that cholinergic modulation may
exert important control on the net output of LH circuits by selective
enhancement of excitatory or inhibitory pathways.
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ACKNOWLEDGMENTS |
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We thank Drs. S. A. Siegelbaum, A. B. MacDermott, and R. Yu for helpful comments on prior versions of this manuscript and T. Davis for technical assistance.
This work was supported by a Grable-Distinguished Investigator Award from National Alliance for Research on Schizophrenia and Depression (NARSAD) and National Institute of Neurological Disorders and Stroke Grant NS-22061 to L. W. Role.
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FOOTNOTES |
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Address for reprint requests: L. W. Role, Columbia University P & S, Center for Neurobiology, 1051 Riverside Drive, P.I. Annex, Room 807, New York, New York 10032 (E-mail: lwr1{at}columbia.edu).
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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7 Nicotinic acetylcholine receptors and modulation of gabaergic synaptic transmission in the hippocampus.
Eur J Pharmacol
393:
59-67, 2000[Web of Science][Medline].This article has been cited by other articles:
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  G. Burnstock Physiology and Pathophysiology of Purinergic Neurotransmission Physiol Rev, April 1, 2007; 87(2): 659 - 797. [Abstract] [Full Text] [PDF]
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 Y.-H. Jo, D. Wiedl, and L. W. Role Cholinergic Modulation of Appetite-Related Synapses in Mouse Lateral Hypothalamic Slice J. Neurosci., November 30, 2005; 25(48): 11133 - 11144. [Abstract] [Full Text] [PDF]
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 K. Kawa Discrete but simultaneous release of adenine nucleotides and serotonin from mouse megakaryocytes as detected with patch- and carbon-fiber electrodes Am J Physiol Cell Physiol, January 1, 2004; 286(1): C119 - C128. [Abstract] [Full Text] [PDF]
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