Valproate modifies spontaneous excitation and inhibition at cortical synapses in vitro.
The anticonvulsant, valproic acid (VPA), has a very wide spectrum of clinical activity and has conventionally been considered to act by enhancing inhibitory GABAergic activity, either by increasing GABA levels and its subsequent release or by enhancing postsynaptic GABA responses. However, the pharmacology of VPA is complex and other mechanisms may well contribute. In the present study, we examined the effect of the drug on the release of GABA and glutamate at synapses in the rat entorhinal cortex, using the whole-cell patch clamp technique to record spontaneous excitatory (sEPSCs) and inhibitory postsynaptic currents (sIPSCs). VPA reduced the frequency but not the amplitude of both spontaneous sEPSCs and sIPSCs, with a more pronounced effect on the former. However, VPA had no effect on miniature, monoquantal events recorded in the presence of TTX, suggesting that the reduction in release occurred via blockade of Na(+)-channels in the presynaptic neurones. In addition, VPA also prolonged the decay time of sIPSCs, and this effect was occluded by a benzodiazepine agonist, zolpidem. These data suggest that in addition to presynaptic effects on release, VPA can potentiate postsynaptic responses, possibly by interaction with the benzodiazepine regulatory site of the GABA(A) receptor.
Department of Physiology and MRC Centre for Synaptic Plasticity, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Mark O
MO
Cunningham
Gavin L
GL
Woodhall
Roland S G
RS
Jones
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D018755:GABA Agonists; D011725:Pyridines; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D000077334:Zolpidem