Valproic acid potently inhibits interictal-like epileptiform activity in prefrontal cortex pyramidal neurons

Abstract

Valproic acid has a long-standing reputation of effectively treating the symptoms of not only epilepsy but also psychiatric conditions. In the latter, the exact mechanism by which valproate exerts its effect remains unclear. In this study, epileptiform bursts were recorded from pyramidal neurons in the prefrontal cortex (the brain region thought to be involved in psychiatric disorders) using the patch-clamp technique. An extracellular solution with no magnesium ions and elevated potassium levels that is known to induce epileptiform activity in vitro was used. Because of their short durations, the epileptiform bursts were regarded as interictal-like epileptiform activity, which is believed to be involved in cognitive impairment. Interictal discharges occur in many neuropsychiatric disorders as well as in healthy population.Epileptic activity in prefrontal cortex pyramidal neurons was potently inhibited by two therapeutic concentrations of valproic acid (20 μM and 200 μM). Moreover, valproate suppressed spontaneous excitatory postsynaptic potentials. Epileptiform bursts were fully inhibited by NMDA receptor antagonist, which suggests that epileptiform activity is driven by NMDA receptors. The inhibition of excitability in prefrontal cortex pyramidal neurons by valproate was also shown.This study shows that it is possible to evoke NMDA-dependent epileptiform activity in prefrontal cortex pyramidal neurons in vitro.We suggest that the prefrontal cortex is a good region for studying the influence of drugs on interictal epileptiform activity.