石杉碱甲增强大鼠海马脑片CA1锥体神经元的兴奋性突触传递

目的:观察石杉碱甲(Hup-A)对海马CA1锥体神经元兴奋性突触传递的影响,以探讨其增强学习记忆功能的神经细胞电生理机制。方法:应用大鼠海马脑片CA1锥体神经元细胞内记录技术,观察Hup-A对大鼠海马CA1锥体神经元膜电性质和刺激Schaffer侧支诱发的兴奋性突触后电位(EPSP)的影响。结果:(1)Hup-A(1μmol/L)灌流15min对CA1锥体神经元的膜电性质没有显著性影响。(2)Hup-A(0.3～3.0μmol/L)浓度依赖性使EPSP幅度升高、时程延长、曲线下面积增大,该作用可被阿托品(10μmol/L)预处理取消。(3)Hup-A对外源性谷氨酸诱导的去极化反应无明显影响。结论:Hup-A可增强CA1锥体神经元的兴奋性突触传递,其增强突触传递作用与M型乙酰胆碱受体激动有关。     

Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission

Previous behavioural and electrophysiological studies have indicated that levetiracetam (ucb LO59) acts as an anticonvulsant drug in vivo. The purpose of the present study was to investigate the effects of levetiracetam on normal synaptic transmission and epileptiform activity in vitro. Intracellular recordings were obtained from the CA3 subfield of the rat hippocampal slice preparation. Levetiracetam in a concentration of 10 μM did not influence basic cell properties or normal synaptic transmission evoked by subthreshold and suprathreshold stimuli to the commissural pathway. However, it strongly inhibited the development of epileptiform bursting by the γ-aminobutyric acid (GABA)_A-receptor antagonist bicuculline (1– 30 μM). Levetiracetam also decreased the size of bursts previously established by bicuculline. In experiments in which the glutamate-receptor agonist N-Methyl-D-Aspartate (NMDA) was used to generate spontaneous bursting, levetiracetam had no effect on the size of the bursts but decreased bursting frequency. The difference in effects of levetiracetam on bicuculline- and NMDA-induced bursting appeared to be dependent on the convulsant used, since in the presence of 10 μM bicuculline, levetiracetam decreased the size of NMDA-bursts to the same extent as the size of synaptically evoked bicuculline-bursts but had little effect on bursting frequency. The results show that under our experimental conditions, levetiracetam did not alter the components of normal synaptic transmission. However, levetiracetam at the concentrations studied inhibited epileptiform bursting induced by bicuculline and NMDA in vitro in a manner consistent with the profile of an antiepileptogenic drug. Received: 27 December 1996 / Accepted: 5 June 1997     

Effects of Cd on AMPA receptor-mediated synaptic transmission in rat hippocampal CA1 area

Cadmium (Cd²⁺) is a common pollutant that causes a wide variety of toxic effects on the central nervous system. However, the mechanism of Cd²⁺ neurotoxicity remains to be elucidated. In the present study, we examined the effects of Cd²⁺ on AMPA receptor-mediated synaptic transmission and short-term synaptic plasticity in hippocampal CA1 area, using whole-cell patch clamp technique. Cd²⁺ significantly inhibited the peak amplitude of evoked EPSCs (eEPSCs) in a concentration-dependent manner and enhanced the short-term synaptic plasticity including paired-pulse facilitation and frequency facilitation. Cd²⁺ also decreased the frequency and amplitude of spontaneous EPSCs (sEPSCs) but had no effect on those of miniature EPSCs (mEPSCs). These effects of Cd²⁺ may involve a presynaptic mechanism of blockade of action potential-sensitive, calcium-dependent release of glutamate. In addition, Cd²⁺ prolonged the decay time of both sEPSCs and mEPSCs, which suggested a postsynaptic action site of Cd²⁺. This study demonstrates that Cd²⁺ impairs the Schaffer collateral-commissural-CA1 glutamatergic synaptic transmission and short-term plasticity in rat hippocampal slices, which may be a possible contributing mechanism for the Cd²⁺-induced neurotoxic effects.     

Excitatory afferents to CA3 pyramidal cells display differential sensitivity to CB1 dependent inhibition of synaptic transmission

Recent advances in immunohistochemical techniques have, contrary to earlier reports, positively identified CB1 receptors on glutamatergic terminals in the hippocampus. Further work has implicated these receptors in modulation of susceptibility to kainic acid induced seizures. Based on these results, the current study was designed to test the hypothesis that both exogenous and endogenous cannabinoids can selectively modulate glutamatergic afferents to CA3 pyramidal cells, and that such modulation is mediated by cannabinoid type 1 (CB1) receptors. Towards that end we employed either conventional or two-photon guided minimal stimulation techniques to isolate mossy fiber and/or associational/commissural (A/C) inputs to CA3 pyramidal cells. We report that bath application of WIN55,212-2 selectively inhibits minimally evoked A/C inputs to CA3 pyramidal cells, without significantly altering simultaneously recorded mossy fiber inputs. Further, we find that WIN55,212-2 mediated inhibition of A/C inputs is completely blocked by the CB1 selective antagonist AM-251 and absent in CB1^−/− animals, suggesting a dependence on CB1 receptors. Finally, we demonstrate that depolarization of CA3 pyramidal cells leads to calcium dependent release of endogenous cannabinoids that transiently inhibit A/C mediated responses, and that this effect is also sensitive to both AM-251 and the muscarinic acetylcholine receptor antagonist atropine. To our knowledge this represents the first demonstration of depolarization induced suppression of excitation in area CA3 of the hippocampus. Collectively, these results provide new information relevant to developing a thorough understanding of how ECs modulate excitatory transmission in an area that is both essential for the acquisition of new memories and intimately involved in epileptogenesis.     

Characterisation of the effects of ATPA,a GLU(K5) receptor selective agonist,on excitatory synaptic transmission in area CA1 of rat hippocampal slices

Kainate receptors are involved in a variety of synaptic functions in the CNS including the regulation of excitatory synaptic transmission. Previously we described the depressant action of the GLU(K5) selective agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA) on synaptic transmission in the Schaffer collateral-commissural pathway of rat hippocampal slices. In the present study we report several new features of the actions of ATPA at this synapse. Firstly, the effectiveness of ATPA is developmentally regulated. Secondly, the effects of ATPA decline during prolonged or repeated applications. Thirdly, the effects of ATPA are not mediated indirectly via activation of GABA(A), GABA(B), muscarinic or adenosine A(1) receptors. Fourthly, elevating extracellular Ca(2+) from 2 to 4 mM antagonises the effects of ATPA. Some differences between the actions of ATPA and kainate on synaptic transmission in the Schaffer collateral-commissural pathway are also noted.     

Triethyltin exposure suppresses synaptic transmission in area CA1 of the rat hippocampal slice

To examine the effects of TET on the electrophysiology of area CA1 of hippocampus, hippocampal slices were obtained from adult hooded rats and were maintained in vitro using standard techniques. Stimulating and recording electrodes were placed in the Schaffer collaterals and CA1 pyramidal cell body layer, respectively. Following baseline measurements, slices were exposed to either 0, 1, 3, 6, or 10 μM TET in the incubating medium. Both pyramidal cell excitability and recurrent/feedforward inhibition were suppressed in a dose-dependent manner within 3 hr postexposure. The evoked population spike and population excitatory postsynaptic potential (EPSP) were suppressed significantly by 2 hr postexposure for 1 and 3 μM TET exposures, and by 45 min postexposure for 6 and 10 μM exposures. A similar dose-dependency was observed for the suppression of recurrent/feedforward inhibition in hippocampal CA1. A second procedure tested the specificity of TET effects to axonal conduction of Schaffer collaterals. Both the stimulating and recording electrode were placed in the Schaffer collaterals so that both the Schaffer collateral population fiber volley and the CA1 pyramidal cell population EPSP could be recorded. TET exposure suppressed pyramidal cell EPSPs without significantly affecting the amplitude of Schaffer collateral fiber volleys. The results support the view that acute TET exposure suppresses synaptic transmission in area CA1 of hippocampus.     

Effects of the Aconitum alkaloid songorine on synaptic transmission and paired-pulse facilitation of CA1 pyramidal cells in rat hippocampal slices

1. The present study investigated the electrophysiological effects of songorine (1–100 μM), an alkaloid occurring in plants of the Aconitum genus, in rat hippocampal slices.
2. Songorine (10–100 μM) evoked a concentration-dependent increase in the amplitude of the orthodromic population spike and in the slope of the field e.p.s.p. The enhancement was long-lasting and was not reversed by up to 90 min of washout. Songorine failed to affect size and shape of the presynaptic fiber spike which represents the compound action potential of the Schaffer collaterals. This indicates that enhancement of the synaptic response is no consequence of an increased afferent excitability.
3. The antidromically evoked population spike was not affected by songorine at concentrations up to 100 μM suggesting that the enhancement of the orthodromic population spike and of the field e.p.s.p. was not due to an increase in pyramidal cell excitability.
4. The input-output curve for the postsynaptic population spike was shifted to the left implying that a presynaptic fiber spike of the same size elicited a larger postsynaptic response, indicating a decrease in threshold for generation of the population spike.
5. The songorine-evoked increase in excitability was not affected by the NMDA receptor antagonist, D-AP5. However, the effect of songorine was completely abolished by the selective dopamine D₂ receptor antagonist sulpiride (0.1 μM) as well as by haloperidol (10 μM) and was mimicked by application of the dopamine releaser, amantadine (100 mM). In contrast, the selective D₁ receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, did not block the action of songorine.
6. The results indicate that the plant alkaloid songorine enhances excitatory synaptic transmission which may be due to an agonistic action at D₂ receptors.

     

Nano-Ag inhibiting action potential independent glutamatergic synaptic transmission but increasing excitability in rat CA1 pyramidal neurons

The aim of this study was to investigate the actions of silver nanoparticles (nano-Ag) on glutamatergic synaptic transmission and excitability in hippocampal CA1 pyramidal neurons with whole cell patch technique. The amplitude of miniature excitatory postsynaptic currents (mEPSCs) was inhibited by silver nano-particles (nano-Ag) (10?? g/ml and 10?? g/ml), but the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) were increased by nano-Ag treatment (10?? g/ml and 10?? g/ml). Furthermore, nano-Ag (10?? g/ml and 10?? g/ml) increased the spontaneous network activity. These results provide further insights into the underlying mechanisms responsible for the effects of nano-Ag on central nervous system (CNS).     

Effects of philanthotoxin-343 on CA1 pyramidal neurons of rat hippocampus in vitro.

A synthetic analog of philanthotoxin-433, philanthotoxin-343 (PhTX-343), was tested in hippocampal pyramidal neurons in vitro. PhTX-343 (2 microM) did not significantly change synaptic transmission mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptors in the CA1 region of hippocampus. However, PhTX-343 significantly suppressed both the synaptic N-methyl-D-aspartate receptor-induced current (NMDA) obtained in the presence of CNQX(6-cyano-7-nitroquinoxaline-2,3-dione)/picrotoxin (10 microM) and the directly evoked NMDA receptor-induced current to pressure ejection of NMDA in the presence of tetrodotoxin (0.5 microM). A short transient facilitation of both types of NMDA response was seen immediately after the beginning of PhTX-343 application. Our results suggest that at high concentration (2 microM) PhTX-343 inhibits the NMDA-gated current, while the early facilitation occurred during an initial low concentration of the compound. Both facilitative and depressive actions of PhTX-343 are localized at the postsynaptic membrane.     

Inhibitory action of adenosine on synaptic transmission in the hippocampus of the guinea pig in vitro

Thin hippocampal slices were prepared from guinea pig brains. the postsynaptic field potential elicited in the pyramidal cell layer of CA3 region by mossy fiber stimulation was reversibly inhibited by application of adenosine to the perfusion medium. Among purine and pyrimidine derivatives, only adenosine and adenine nucleotides depressed the field potential with similar dose-response curves at concentrations of 10(-5).10(-3) M. In order to elucidate the mechanism of the inhibitory action of these agents, the effects of adenosine and adenine nucleotides on membrane events in pyramidal neurons were studied using intracellular recording techniques. Application of adenosine and adenine nucleotides hyperpolarized membrane potential and markedly depressed the EPSPs (excitatory postsynaptic potentials) elicited in the pyramidal cell by granular cell activation. However the spike generating mechanism of the neuron was not interfered with and membrane conductance was not increased by adenosine and adenine nucleotides. 4-Aminopyridine counteracted the inhibitory action of adenosine. These findings indicate that the mechanism of the inhibitory action of adenosine and adenine nucleotides is different from that of conventional inhibitory neurotransmitters such as gamma-aminobutyric acid and suggest a presynaptic action of adenosine and adenine nucleotides.     

Effects of Cd(2+) on AMPA receptor-mediated synaptic transmission in rat hippocampal CA1 area

Deoxynivalenol (DON), a mycotoxin produced by some Fusarium species, is a frequent contaminant of cereals. This toxin is known to modulate the immune function but only few studies have investigated the effect of DON on the vaccinal immune response. In the present experiment, 24 pigs received for 9 weeks either control feed or feed naturally contaminated with 2.2-2.5 mgDON/kg feed. At days 4 and 15 of the experiment, the animals were subcutaneously immunized with ovalbumin. Consumption of DON-contaminated diet does not have a major effect on the hematological and biochemical blood parameters. By contrast, ingestion of DON significantly affects the global and the specific immune response of the pigs. In the serum, DON increases the concentration of total IgA and, in vaccinated animals, DON also increases the concentration of ovalbumin-specific IgA and IgG. DON does not modulate lymphocytes proliferation after mitogenic stimulation but the toxin had a biphasic effect on lymphocyte proliferation after antigenic stimulation (up-regulation at day 21 and down-regulation at day 35-49). Because cytokines play a key role in immunity, the expression levels of TGF-beta, IFN-gamma, IL-4 and IL-6 were measured, by RT-PCR in the spleen, the ileum and the mesenteric lymph node of the animals at the end of the experiment. In the mesenteric lymph node, a significantly lower expression of both TGF-beta and IFN-gamma mRNA expression levels is observed in animals feed with DON when compared with control piglets. Taken together, our data indicate that DON alters the vaccinal immune response. These results may have implications for humans and animals consuming DON-contaminated food or feed as breakdown in vaccinal immunity may lead to the occurrence of disease even in properly vaccinated populations.     

Electrophysiological actions of cyclosporin A and tacrolimus on rat hippocampal CA1 pyramidal neurons

Aim： The aim of the present study was to investigate the electrophysiological actions of cyclosporin A （CsA） and tacrolimus （FK506） on neurons in the brain, and to elucidate the relevant mechanisms. Methods： Whole-cell current-clamp recording was made in CA1 pyramidal neurons in rat hippocampal slices; whole- cell voltage-clamp recording was made in dissociated hippocampal CA1 pyrami- dal neurons of rats. Results： CsA （100 prnol/L） and FK506 （50 prnol/L） did not significantly alter the passive electrical properties of hippocampal CA 1 pyramidal neurons, but slowed down the repolarizing phase of the action potential. CsA （10-100 lamol/L） selectively inhibited the delayed rectifier K~ current （IK） in a concentration-dependent manner. CsA did not affect the kinetic properties of IX. Intracellular dialysis of CsA （100 prnol/L） had no effect on Ix. The inhibition ofIK by CsA （100 lamol/L） persisted under the low Ca^2＋ conditions that blocked the basal activity of calcineurin. Conclusion： CsA exerted calcineurin-independent inhibition on the Ix in rat hippocampal pyramidal neurons. Taken together with our previous finding with FK506, it is conceivable that the spike broadening caused by the immunosuppressant drugs is due to direct inhibition on the Ix.     

Adenosine A(1)-receptor-mediated tonic inhibition of glutamate release at rat hippocampal CA3-CA1 synapses is primarily due to inhibition of N-type Ca(2+) channels

The voltage-gated Ca(2+) channels responsible for synaptic transmission at CA3-CA1 synapses are mainly P/Q- and N-types. It has been shown that tonic inhibition of transmission due to activation of adenosine A(1) receptors occurs at this synapse. We have recently developed a technique to monitor synaptically released glutamate which is based on synaptically induced glial depolarisation. Using this technique, we have examined the effects of different voltage-gated Ca(2+) channel blockers on glutamate release. Under conditions in which the adenosine A(1) receptor was not blocked, omega-AgaIVA (a P/Q-type voltage-gated Ca(2+) channel blocker) suppressed synaptically induced glial depolarisation to a greater extent than omega-CgTxGVIA (an N-type voltage-gated Ca(2+) channel blocker) did. In contrast, in the presence of an adenosine A(1) receptor antagonist, omega-AgaIVA was less effective at suppressing synaptically induced glial depolarisation than omega-CgTxGVIA. These results indicate that, in the absence of adenosine A(1) receptor-mediated tonic inhibition, the contribution of N-type is much greater than that of P-type, and that N-types are the primary target of tonic inhibition in normal conditions in which adenosine A(1) receptor-mediated tonic inhibition is present.     

Pharmacological characterization of presynaptic α-adrenoceptors modulating [3H]noradrenaline and [3H]5-hydroxytryptamine release from slices of the hippocampus of the rat

The experiments served to characterize the receptors mediating the inhibitory effect of α-adrenergic drugs on K⁺ (20 mM)-induced [³H]noradrenaline (NA) and [³H]5-hydroxytryptamine ([³H]5-HT) release from slices of the dorsal part of rat hippocampus. Dose-response curves were constructed using the cumulative dose-response technique (Frankhuyzen and Mulder, 1982). All of the adrenergic agonist drugs examined inhibited the K⁺-induced [³H]NA release. NA appeared to have the highest intrinsic activity followed by adrenaline. Clonidine and adrenaline had similar intrinsic activities, while that of oxymetazoline was lowest. The highest pD₂ values were observed for oxymetazoline and clonidine, being slightly higher than that of adrenaline followed by NA. By far the lowest pD₂ values was observed for phenylephrine. With the exception of phenylephrine, all of the agonists also inhibited the K⁺-induced [³H]5-HT release. NA, adrenaline and oxymetazoline appeared to have similar intrinsic activities, while that of clonidine was considerably lower. The pD₂ values of NA and adrenaline were not significantly different but were somewhat lower than those of oxymetazoline and clonidine. Similar antagonistic effects of phentolamine and yohimbine were observed with respect to the adrenergic inhibition of K⁺-induced [³H]NA and [³H]5-HT release. Prazosin, however, appeared to be ineffective in both instances. It is concluded from these results that the presynaptic adrenergic inhibition of [³H]NA as well as [³H]5-HT release is mediated by α₂-adrenoceptors located on noradrenergic and serotonergic varicosities, respectively. Furthermore, our data suggest that these α₂-adrenoceptors are not pharmacologically identical.     

The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1

Riluzole is believed to exert its anticonvulsant and neuroprotective actions by reducing glutamate release. This study demonstrated that 10–30 μM riluzole reduces the K⁺-evoked release of glutamate and aspartate from slices of hippocampal area CA1. Only higher concentrations reduced γ-aminobutyrate (GABA) release. These actions of riluzole were not occluded by tetrodotoxin. Riluzole did not diminish the ability of glutamate analogues to depolarize CA1 pyramidal cells, as determined from grease-gap recordings. Therefore the anticonvulsant and neuroprotective actions of riluzole in the hippocampus may be at least partly explained by its ability to inhibit glutamate/aspartate release from synaptic terminals.     

石杉碱甲对大鼠海马脑片CA1神经元θ节律及长时程增强的影响

目的:研究石杉碱甲(HupA)对大鼠海马脑片CA1锥体神经元θ节律、长时程增强的影响,以分析其增强学习记忆功能的神经细胞电生理机制。方法:应用大鼠海马脑片神经元细胞内记录技术,观察石杉碱甲对大鼠海马脑片的CA1锥体神经元θ节律、长时程增强的影响。结果:(1)未用药组出现膜电位振荡前后4～10Hz(θ节律)功率分量之和无显著性差异,但在HupA(1μmol·L-1)灌流15min后出现膜电位振荡,与用药前没有膜电位振荡的4～10Hz功率分量之和配对t检验比较有显著差异(n=3,P<0.005)。(2)在LTP期间,对照组EPSP幅度在强直刺激后30min显著性的升高(P<0.05),而HupA组在强直刺激后15min即出现显著性升高(P<0.01)。结论:HupA可增加大海马锥体神经元在θ频率范围内的功率分量,并易化LTP的诱发,这可能是其增强学习记忆功能的细胞电生理机制之一。     

Dopamine selectively potentiates hippocampal mossy fiber to CA3 synaptic transmission

Dopamine has been implicated in various brain functions and the pathology of neurological diseases. In the hippocampus, dopamine has been shown to induce acute depression of synaptic transmission in the CA1 region, but it remains largely unknown how it works in the CA3 region. We here report that dopamine induces acute synaptic potentiation at the synapse formed by mossy fibers (MFs) on mouse hippocampal CA3 pyramidal cells, but not at converging associational/commissural synapses. Dopamine potentiated both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) components of MF synaptic responses similarly in respect of the magnitude and time course. The dopamine-induced potentiation was intact in the presence of picrotoxin, required activation of D(1)-like receptors and was apparently occluded by an activator of adenylate cyclase. The potentiation was accompanied by a decrease in magnitude of synaptic facilitation, suggesting the presynaptic site for the expression of the potentiation. The present study is the first demonstration of acute potentiation of hippocampal excitatory synaptic transmission by dopamine, which is most probably mediated by presynaptic D(1)-like receptor-cAMP cascades.     

Inhibition of hyperpolarization-activated cation currents by phencyclidine and some sigma ligands in rat hippocampal CA1 pyramidal neurons in vitro

Using whole-cell voltage-clamp recordings, hyperpolarization-activated cation currents (Ih) were elicited with hyperpolarizing voltage jumps in CA1 pyramidal neurons of rat hippocampal slices, and the effects of phencyclidine (PCP) and some sigma ligands on Ih were studied. PCP concentration-dependently (0.1-100 microM) suppressed Ih and shifted the activation curve of Ih to the negative direction. D-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 20 microM) and MK-801 (30 microM), competitive and non-competitive NMDA blockers, respectively, failed to mimic the inhibitory effect of PCP on Ih, and suppression of Ih by PCP was unaffected in the presence of these blockers. To explore the involvement of sigma1 receptors in the reduction of Ih, the effects of representative sigma1 ligands were studied. SKF10047 (100 microM), a sigma1 agonist, attenuated the maximal Ih and shifted the half-activation potential of Ih to the hyperpolarized direction. In the presence of the sigma1 antagonist NE-100 (1 microM), which alone did not affect Ih, the effect of SKF10047 on Ih was unaltered. By contrast, a higher concentration of NE-100 (10 microM) mimicked the effect of SKF10047. Again, no antagonism of Ih suppression by SKF10047 was obtained with rimcazole (100 microM), a sigma1 receptor antagonist that is structurally distinct from NE-100. This concentration of rimcazole alone resulted in a slight but significant reduction of Ih. Thus these major sigma1 ligands appear to suppress Ih independently of their agonistic or antagonistic properties. The results of this study suggest that PCP and some sigma ligands could modulate cell excitability partly through their action on Ih.     

Valproate reduced excitatory postsynaptic currents in hippocampal CA1 pyramidal neurons

Valproate (VPA) is one of the most widely used antiepileptic drugs, and it is also increasingly used for the treatment of neuropsychological disorders and neuropathic pain, as well as migraine prophylaxis. However, the underlying cellular mechanisms of VPA on the synaptic physiology remain unclear. We investigated the effects of VPA on synaptic transmission using the in vitro rat hippocampal slice technique and whole-cell patch clamp recordings from CA1 pyramidal neurons. Perfusion with VPA, at therapeutically attainable concentrations, decreased the amplitude of excitatory postsynaptic currents (EPSCs) evoked by Schaffer collateral stimulation, without modifying inhibitory postsynaptic currents (IPSCs). Furthermore, VPA induced a significant reduction of the non-NMDA EPSC (non-NMDA(EPSC)) component, without modifying the NMDA EPSC (NMDA(EPSC)) component. Paired pulse facilitation and EPSC variance were not significantly affected by VPA, indicating that VPA did not decrease transmitter release probability, which suggests a postsynaptic mechanism of action. We therefore conclude that VPA decreases excitatory synaptic activity through the modulation of postsynaptic non-NMDA receptors, without modifying synaptic inhibition, and that this reduction of excitation is, at least in part, responsible for the effects of VPA.     

Interaction of diazepam with synaptic transmission in the in vitro rat hippocampus

Summary Diazepam (5×10^–8–10^–6 M) was found to augment recurrent inhibition of pyramidal neuron firing in a dose-dependent manner in rat hippocampal slices. To determine possible loci of this effect, diazepam was locally administered by pressure ejection from a micropipette, while recording action potentials from single inhibitory (basket) interneurons. Diazepam induced reversible and reliable increases in interneuron firing in response to stimulation of Schaffer collateral and commissural afferents. Taken together with previous electrophysiological reports, these data suggest that benzodiazepines may augment central inhibition by increasing either the excitability of inhibitory interneurons, or by increasing the strength of excitatory afferents to these cells.