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PubMed2002

Post-tetanic depression of GABAergic synaptic transmission in rat hippocampal cell cultures.

The effect of tetanic stimulation (30 Hz, 4 s) on evoked GABAergic inhibitory postsynaptic currents (IPSCs) was studied in cell cultures of dissociated hippocampal neurons with established synaptic connections. It was found that tetanic stimulation elicited post-tetanic depression (PTD) of the evoked IPSCs with a duration of more than 50 s in about 60% of the connections tested; post-tetanic potentiation was induced in 25% of the connections. We propose that the opposite effects of tetanization on IPSC amplitude are due to differences in the type of the interneuron that was tetanized. Since PTD in our experiments was usually accompanied by changes in the IPSC coefficient of variation and changes of a paired pulse depression, which are thought to reflect presynaptic mechanisms of modulation, we suggest that part of the PTD is due to a presynaptic mechanism(s).

Animals↗
PubMed1999

Rat hippocampal neurons maintain their own GABAergic synaptic transmission in culture.

The whole-cell patch-clamp technique was used to record monosynaptic inhibitory postsynaptic currents (IPSCs) from pairs of hippocampal neurons cultured for 2-3 weeks. The application of fresh physiological solution for 2-3 min reversibly reduced the amplitude of evoked GABAergic IPSCs to 72.5% of control value. The amplitude and frequency of spontaneous IPSCs decreased too. The depression of evoked IPSCs was significantly smaller or absent if conditioned solution was applied (physiological solution which had been previously in contact with neurons for 30 min). Currents evoked by exogenously applied GABA were unaffected by fresh solution. These results suggest that hippocampal neurons release some endogenous substance(s), by which they up regulate presynaptically their own inhibitory synaptic transmission.

Animals↗
PubMed2003

Retrograde signaling changes the venue of postsynaptic inhibition in rat substantia nigra.

Both endocannabinoids through cannabinoid receptor type I (CB1) receptors and dopamine through dopamine receptor type D1 receptors modulate postsynaptic inhibition in substantia nigra by changing GABA release from striatonigral terminals. By recording from visually identified pars compacta and pars reticulata neurons we searched for a possible co-release and interaction of endocannabinoids and dopamine. Depolarization of a neuron in pars reticulata or in pars compacta transiently suppressed evoked synaptic currents which were blocked by GABA(A) receptor antagonists (inhibitory postsynaptic currents [IPSCs]). This depolarization-induced suppression of inhibition (DSI) was abrogated by the cannabinoid CB1 receptor antagonist AM251 (1 microM). A correlation existed between the degree of DSI and the degree of reduction of evoked IPSCs by the CB1 receptor agonist WIN55,212-2 (1 microM). The cholinergic receptor agonist carbachol (0.5-5 microM) enhanced DSI, but suppression of spontaneous IPSCs was barely detectable pointing to the existence of GABA release sites without CB1 receptors. In dopamine, but not in GABAergic neurons DSI was enhanced by the dopamine D1 receptor antagonist SCH23390 (3-10 microM). Both the antagonist for CB1 receptors and the antagonist for dopamine D1 receptors enhanced or reduced, respectively, the amplitudes of evoked IPSCs. This tonic influence persisted if the receptor for the other ligand was blocked. We conclude that endocannabinoids and dopamine can be co-released. Retrograde signaling through endocannabinoids and dopamine changes inhibition independently from each other. Activation of dopamine D1 receptors emphasizes extrinsic inhibition and activation of CB1 receptors promotes intrinsic inhibition.

Animals↗
PubMed1997

Heterogeneity of functional synaptic parameters among single release sites.

Following alpha-latrotoxin application to cerebellar slices, bursts of miniature IPSCs (mIPSCs) were observed in interneurons of the molecular layer. Within bursts, mIPSCs had homogeneous amplitudes with a narrow Gaussian distribution. Analysis of successive event amplitudes revealed an interaction between consecutive IPSCs, indicating that bursts originate at single release sites. A mean receptor occupancy of 76% was calculated. IPSCs within a burst were analyzed using nonstationary noise analysis. The results indicate that individual release sites differ in the number, unitary conductance, and peak opening probability of their postsynaptic channels. In addition, the IPSC decay kinetics were very different among release sites. Finally, a significant correlation was found between several pairs of single site synaptic parameters.

Animals↗
PubMed2000

Interactions between distinct GABA(A) circuits in hippocampus.

Synchronous activity among synaptically connected interneurons is thought to organize temporal patterns such as gamma and theta rhythms in cortical circuits. Interactions between distinct interneuron circuits may underlie more complex patterns, such as nested rhythms. Here, we demonstrate such an interaction between two groups of CA1 interneurons, GABA(A,slow) and GABA(A,fast) cells, that may contribute to theta and gamma rhythms, respectively. Stratum lacunosum-moleculare (SL-M) stimuli that activate GABA(A,slow) inhibitory postsynaptic currents (IPSCs) in pyramidal cells simultaneously depress the rate and amplitude of spontaneous GABA(A,fast) IPSCs for several hundred milliseconds. This suppression has a similar pharmacological profile to GABA(A,slow) IPSCs, and SL-M stimuli elicit GABA(A,slow) IPSCs in interneurons. We conclude that GABA(A,slow) cells inhibit both pyramidal cells and GABA(A,fast) interneurons and postulate that this interaction contributes to nested theta/gamma rhythms in hippocampus.

Animals↗
PubMed1998

Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry.

Divergence and convergence of synaptic connections make a crucial contribution to the information processing capacity of the brain. Until recently, it was thought that transmitter released at a synapse affected only a specific postsynaptic cell. We show here that spillover of inhibitory transmitter at the Golgi to granule cell synapse produces significant cross-talk to non-postsynaptic cells, which is promoted both by the anatomical specialization of this glomerular synapse and by the presence of the high affinity alpha6 subunit-containing GABA(A) receptor in granule cells. Cross-talk is manifested as a novel slow rising and decaying small amplitude inhibitory postsynaptic current (IPSC) that can also contribute a long-lasting component to more typical IPSCs, which is prolonged by inhibition of the neuronal GABA transporter GAT-1. Because of the long duration of IPSCs generated by spillover, the total charge carried is three times that of IPSCs generated by directly connected terminals. GABA spillover within the mossy fiber glomerulus may play an important role in regulating the number of granule cells active in the cerebellar cortex, a regulation that is suggested by theoretical models to optimize cerebellar information processing.

Animals↗
PubMed2004

Maintenance of high-frequency transmission at purkinje to cerebellar nuclear synapses by spillover from boutons with multiple release sites.

Cerebellar Purkinje neurons maintain high firing rates but their synaptic terminals depress only moderately, raising the question of how vesicle depletion is minimized. To identify mechanisms that limit synaptic depression, we evoked 100 Hz trains of GABAergic inhibitory postsynaptic currents (IPSCs) in cerebellar nuclear neurons by stimulating Purkinje axons in mouse brain slices. The paired-pulse ratio (IPSC(2)/IPSC(1)) of the total IPSC was approximately 1 and the steady-state ratio (IPSC(20)/IPSC(1)) was approximately 0.5, suggesting a high response probability of postsynaptic receptors, without an unusually high release probability. Three-dimensional electron microscopic reconstructions of Purkinje boutons revealed multiple active zones without intervening transporters, suggestive of "spillover"-mediated transmission. Simulations of boutons with 10-16 release sites, in which transmitter from any site can reach all receptors opposite the bouton, replicated multiple-pulse depression during normal, high, and low presynaptic Ca influx. These results suggest that release from multiple-site boutons limits depletion-based depression, permitting prolonged, high-frequency inhibition at corticonuclear synapses.

Animals↗
PubMed1996

Review of the role of inhibitory neurons in chronic epileptic foci induced by intracerebral tetanus toxin.

Blocking inhibition provides one of the most common experimental means of triggering epileptic activity in hippocampus and neocortex. However, it has proved much more difficult to show that chronic models of epilepsies are due to disinhibition. One problem is knowing how much inhibition needs to be blocked to provide a sufficient mechanism for epileptic activity. We have found that inhibitory (GABAA) transmission, estimated from evoked monosynaptic IPSCs, must be reduced to 17% of their control amplitude (by 4-7 microM bicuculline) before hippocampal slices generate all-or-none epileptic discharges. Similar estimates of inhibition in chronic epileptic foci induced by intrahippocampal injection of tetanus toxin showed that monosynaptic IPSCs dropped to 10% of control in the injected hippocampus during the first 2 weeks after injection. At all other stages of the active epileptic foci in the two hippocampi the reduction in IPSCs was not alone sufficient for epileptic activity; at 4-6 weeks IPSCs were normal despite continued epileptic activity. One likely mechanism for the late epileptic activity is a reduction of either the intrinsic excitability, or the synaptic excitation, of inhibitory interneurons so they fail to be recruited normally. Alternative mechanisms include the formation of new excitatory connections, as found at modest levels in the dentate gyrus. Several mechanisms may play a part in chronic foci such as those induced by tetanus toxin, either acting together, or sequentially during the progression of the epileptic focus.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro.

1. The rostral ventromedial medulla (RVM) is thought to play a crucial role in the antinociceptive actions of cannabinoids. This study examined the actions of the cannabinoid receptor agonist, WIN55,212-2, on membrane properties and GABAergic synaptic transmission in RVM neurons using whole cell patch clamp recordings in brain slices. 2. WIN55,212-2 (3 microM) had no effect on membrane K+ conductance of primary or secondary RVM neurons. Primary neurons responded to the kappa-opioid receptor agonist U69,593 (300 nM - 1 microM). Secondary neurons responded to the mu,delta-opioid receptor agonist met-enkephalin (10 microM). 3. WIN55,212-2 reduced the amplitude of electrically evoked (GABAergic) inhibitory postsynaptic currents (IPSCs) in all neurons (58%, pEC50=6.2+/-0.1). The inhibition was reversed by the CB1 receptor selective antagonist, SR141716 (3 microM). WIN55,212-2 also produced relative facilitation of the second IPSC to paired evoked IPSCs. 4. WIN55,212-2 and met-enkephalin reduced the rate of spontaneous miniature IPSCs in all cells (44 and 53%), but had no effect on their amplitude distributions or kinetics. 5. These results suggest that the antinociceptive actions of cannabinoids within RVM are primarily due to presynaptic inhibition of GABAergic neurotransmission. The neuronal substrates of cannabinoid actions in RVM therefore differ from those of opioids, which have both pre- and postsynaptic inhibitory actions.

Analgesics↗
PubMed2002

Aconitine facilitates spontaneous transmitter release at rat ventromedial hypothalamic neurons.

The effects of aconitine, an Aconitum alkaloid, on spontaneous inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs respectively) were investigated in the mechanically dissociated rat ventromedial hypothalamic (VMH) neurons in which native presynaptic nerve terminals remained intact. Under current-clamp conditions, aconitine (3 x 10(-6) M) depolarized the neuron with generating the action potentials. The aconitine-induced depolarization was markedly suppressed in the presence of CNQX but it was facilitated in the presence of bicuculline, suggesting that release of excitatory and inhibitory neurotransmitters may be involved in the aconitine action in addition to its direct action on postsynaptic membrane. Under the voltage-clamp conditions, aconitine reversibly increased the frequency of spontaneous IPSC and EPSC frequency, but it did not alter their amplitude distribution. Tetrodotoxin (TTX, 3 x 10(-7) M) completely abolished the aconitine action on spontaneous IPSC frequency. Likewise removal of extracellular Na(+) completely suppressed the aconitine action. Both Ca(2+)-free external solution or addition of 10(-4) M Cd(2+) to normal solutions eliminated the facilitatory effect of aconitine on the IPSC frequency. Overall these results suggest that aconitine depolarizes the presynaptic membrane by activating voltage-dependent Na(+) channels. Increase of intraterminal Ca(2+) concentration via an activation of voltage-dependent Ca(2+) channels in turn enhances the spontaneous transmitter release from presynaptic nerve terminals. The presynaptic action of aconitine may play a crucial role for membrane excitability of rat VMH neurons.

Aconitine↗
PubMed2003

Effects of endomorphin on substantia gelatinosa neurons in rat spinal cord slices.

1. Whole-cell patch recordings were made from substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of 15- to 30-day-old rats. 2. Endomorphin 1 (EM-1) or EM-2 (<or=10 microM) hyperpolarized or induced an outward current in 26 of the 66 SG neurons. The I-V relationship showed that the peptide activates an inwardly rectifying K+ current. 3. EM-1 or EM-2 (0.3-10 microM) suppressed short-latency excitatory postsynaptic currents (EPSCs) and long-latency inhibitory postsynaptic currents (IPSCs) in nearly all SG neurons tested or short-latency IPSCs in six of the 10 SG neurons. [Met5] enkephalin or [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (1-10 microM) depressed EPSCs and IPSCs. EM-1 or EM-2 depressed synaptic responses without causing a significant change in holding currents or inward currents induced by glutamate. 4. Glutamate also evoked a short-latency outward current in five SG neurons or a biphasic current in two neurons; the outward current was blocked by tetrodotoxin (TTX, 0.3 microM) or bicuculline (10 microM). 5. EM-1 or DAMGO (1 or 5 microM) attenuated the glutamate-evoked outward or biphasic currents in four of the seven SG neurons. EM-1 (1 microm) reduced the frequency, but not the amplitude of miniature EPSCs or miniature IPSCs. 6.. Naloxone (1 microM) or the selective micro-opioid receptor antagonist beta-funaltrexamine (beta-FNA, 25 microM) antagonized the action of EM; EM-induced hyperpolarizations persisted in the presence of the kappa-opioid receptor antagonist (nor-binaltorphimine dihydrochloride, 1 microM) and/or sigma-opioid receptor antagonist (naltrindole hydrochloride, 1 microM). 7. It may be concluded that EM acting on micro-opioid receptors hyperpolarizes a population of SG neurons by activating an inwardly rectifying K+ current, and attenuates excitatory and inhibitory synaptic currents evoked in a population of SG neurons, probably by a presynaptic site of action.

Animals↗
PubMed2004

Cellular actions of somatostatin on rat periaqueductal grey neurons in vitro.

Functional studies indicate that the midbrain periaqueductal grey (PAG) is involved in the analgesic actions of somatostatin; however, the cellular actions of somatostatin in this brain region are unknown. In the present study, whole-cell patch clamp recordings were made from rat PAG neurons in vitro. In 93% of acutely isolated neurons, somatostatin inhibited Ca(2+)-channel currents. This effect was mimicked by the sst-2 selective agonist BIM-23027, but not by the sst-1 and sst-5 selective agonists CH-275 and L-362855. In brain slices, 81% of neurons responded to somatostatin (300 nm) with an increase in K(+) conductance that reversed polarity at -114 mV. A greater proportion of somatostatin-sensitive neurons (93%) than somatostatin-insensitive neurons (53%) responded to the opioid agonist met-enkephalin (10 microm). Somatostatin also reduced the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs). The actions of somatostatin in brain slices were mimicked by BIM-23027, but not by CH-275. Somatostatin had a variable effect on the rate of spontaneous miniature IPSCs in normal external potassium solutions. In high external potassium solutions, somatostatin reduced the rate of miniature IPSCs in all neurons, and this inhibition was abolished by addition of Cd(2+) (30 microm). Somatostatin had no effect on the amplitude of miniature IPSCs. These results indicate that somatostatin acts via sst-2 receptors to directly inhibit a subpopulation of PAG neurons by activating a potassium conductance and inhibits GABA release within PAG via a presynaptic Ca(2+)-dependent mechanism. Thus, like opioids, somatostatin has the potential to exert pre- and postsynaptic disinhibitory effects within the PAG.

Animals↗
PubMed2001

Electrophysiological analysis of suprachiasmatic nucleus projections to the ventrolateral preoptic area in the rat.

The circadian pacemaker housed in the suprachiasmatic nucleus (SCN) synchronizes daily sleep-wake cycles, presumably by modulating the sleep-wake regulatory system, including ventrolateral preoptic area (VLPO) neurons. We used whole-cell patch-clamp recording to study the projections from the SCN to the VLPO in horizontal slices of rat hypothalamus. Single-pulse stimulation of the SCN region elicited postsynaptic currents (PSCs) in 20 of 66 neurons (30%) recorded within the VLPO region as verified by intracellular biocytin labelling. At a holding potential of -60 mV, the evoked PSCs had an amplitude of 17.6 +/- 3.2 pA (SEM) and a latency of 6.3 +/- 0.5 ms (n = 10). There was a trend for simple excitatory postsynaptic currents (EPSCs) to be evoked in the VLPO cluster, simple inhibitory postsynaptic currents (IPSCs) in the extended VLPO, and a combination of EPSCs and IPSCs in both regions. IPSCs were blocked reversibly by bicuculline (10 microm, n = 11). In both the presence and absence of bicuculline, EPSCs had fast and slow components that were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 microm; n = 7), and (+/-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 10 microm, n = 6), respectively. Reversal potentials for the evoked IPSCs and EPSCs were consistent with mediation via GABAA and ionotropic glutamate receptors, respectively. These results suggest that the SCN region provides both inhibitory and excitatory inputs to single VLPO neurons, which are mediated, respectively, by GABAA receptors and by both non-NMDA and NMDA glutamate receptors. These projections may play important roles in conveying circadian input to systems in the preoptic area that regulate sleep and waking.

Animals↗
PubMed2000

Metabotropic glutamate receptors and blockade of glial Krebs cycle depress glycinergic synaptic currents of mouse hypoglossal motoneurons.

Metabotropic glutamate receptors are known to depress synaptic transmission by inhibiting transmitter release from presynaptic nerve terminals. This study reports the effects of presynaptic metabotropic glutamate receptor activation on inhibitory synaptic transmission in hypoglossal motoneurons in brainstem slice preparations of neonatal mice. Whole-cell patch-clamp recordings were performed on hypoglossal motoneurons of 2-6-day-old mice. Monosynaptic glycinergic currents were elicited by electrical stimulation of the nucleus of Roller. Application of the specific metabotropic glutamate receptor agonists (+/-)-1-aminocyclopentane-trans-1,3,dicarboxylic acid (t-ACPD), (2S, 2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)-glycine (DCG-IV) or L-2-amino-4-phosphonobutyric acid (L-AP4) depressed stimulus-evoked glycinergic inhibitory postsynaptic currents (IPSCs) by an average of 39.5, 59.4 and 39.2%, respectively. In the presence of t-ACPD, glycinergic miniature IPSCs were reduced in frequency but not in amplitude, which is indicative of a presynaptic mechanism. A similar reduction of IPSC amplitude was observed in the presence of elevated extracellular glutamate or during application of D, L-threo-hydroxyaspartate (THA), a blocker of glutamate transport, respectively. The data suggest that uptake of glutamate, which is predominately carried out by glial cells, can prevent spill-over of glutamate and activation of metabotropic glutamate receptors. A reduction of IPSCs was also observed following application of monofluoroacetic acid, a substance acting specifically on glial cells. Our results suggest that glial regulation of extracellular glutamate uptake can prevent spill-over of glutamate, and glutamatergic depression of glycinergic inhibition in hypoglossal motoneurons.

Animals↗
PubMed2002

Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids.

It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10(-6) and 10(-5) m). The CB1 cannabinoid receptor antagonist SR141716A (10(-6) m) prevented the inhibition produced by WIN55212-2 (10(-5) m). Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212-2 (10(-5) m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212-2 (10(-5) m). The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase.

Analgesics↗
PubMed2002

Kindling enhances kainate receptor-mediated depression of GABAergic inhibition in rat granule cells.

Several lines of evidence indicate a substantial contribution of kainate receptors to temporal lobe seizures. The activation of kainate receptors located on hippocampal inhibitory interneurons was shown to reduce GABA release. A reduced GABA release secondary to kainate receptor activation could contribute to an enhanced seizure susceptibility. As the dentate gyrus serves a pivotal gating function in the spread of limbic seizures, we tested the role of kainate receptors in the regulation of GABA release in the dentate gyrus of control and kindled animals. Application of glutamate (100 micro m) in the presence of the NMDA receptor antagonist d-APV and the AMPA receptor antagonist, SYM 2206 caused a slight depression of evoked monosynaptic inhibitory postsynaptic currents (IPSCs) in control, but a substantial decrease in kindled dentate granule cells. The observation that kainate receptor activation altered paired-pulse depression and reduced the frequency of TTX-insensitive miniature IPSCs without affecting their amplitude is consistent with a presynaptic action on the inhibitory terminal to reduce GABA release. In kindled preparations, neither glutamate (100 micro m) nor kainate (10 micro m) applied in a concentration known to depolarize hippocampal interneurons led to an increase of the TTX-sensitive spontaneous IPSC frequency nor to changes of the postsynaptic membrane properties. Consistently, the inhibitory effect on evoked IPSCs was not affected by the presence of the GABAB receptor antagonist, CGP55845A, thus excluding a depression by an enhanced release of GABA acting on presynaptic GABAB receptors. The enhanced inhibition of GABA release following presynaptic kainate receptor activation favours a use-dependent hyperexcitability in the epileptic dentate gyrus.

Animals↗
PubMed2003

Dopamine receptor supersensitivity in rat subthalamus after 6-hydroxydopamine lesions.

The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta, but the importance of this input in the pathophysiology of parkinsonism remains to be determined. We used whole-cell patch-clamp recordings in brain slices to study presynaptic dopaminergic modulation of synaptic inputs to the STN in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Here, we report that dopamine was more potent for inhibiting GABA IPSCs and glutamate EPSCs in the STN ipsilateral to the lesion, and was less potent for suppressing IPSCs and EPSCs in the STN contralateral to the lesion, compared with the effects of dopamine in control STN. Dopamine reduced IPSCs with an IC50 value of 20.9 +/- 3.6 microM in control STN, whereas IC50 values were 0.83 +/- 0.15 and 55.1 +/- 11.1 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Dopamine also inhibited EPSCs with an IC50 value of 12.8 +/- 2.8 microM in control STN, whereas IC50 values were 4.5 +/- 0.9 and 41.6 +/- 9.8 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Results with paired stimuli to evoke EPSCs and IPSCs suggest that endogenous dopamine acts presynaptically to inhibit transmitter release in the STN. These results show that chronic dopamine denervation significantly alters the regulation of synaptic input to the STN. Our results also suggest that the STN may be an important target for levodopa therapy in Parkinson's disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Elevation of basal protein kinase C activity increases ethanol sensitivity of GABA(A) receptors in rat hippocampal CA1 pyramidal neurons.

The ability of ethanol to enhance GABA(A) receptor function remains controversial; conflicting observations have been made even in the same brain region, and when using apparently similar methodologies. In this study we characterized a single protocol variable, the initial incubation temperature of brain slices, that had dramatic effects on the ethanol sensitivity of GABA(A) inhibitory postsynaptic currents (IPSCs) recorded from rat hippocampal CA1 pyramidal neurons. Incubation of hippocampal slices at relatively low temperatures (11-15 degrees C) immediately after slice preparation significantly affected a number of physiological and biochemical parameters. Such slices showed a decrease in extracellular inhibitory postsynaptic potential amplitude, a significant increase in the ethanol sensitivity of GABA(A) IPSCs in CA1 pyramidal neurons, no change in pentobarbital or flunitrazepam potentiation of IPSCs, and an increase in basal protein kinase C (PKC) activity relative to slices incubated at 31-33 degrees C. In addition, the increase in ethanol sensitivity of GABA(A) IPSCs was blocked by chelerythrine, a selective inhibitor of PKC. These results suggest that differences in hippocampal slice incubation protocols may have contributed to the disparate results of previous investigations of ethanol modulation of GABA(A) receptor-mediated synaptic transmission in the rat hippocampus. In addition, these findings provide further evidence that PKC activity positively modulates the interaction between ethanol and GABA(A) receptors in the mammalian brain.

Animals↗