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. (C) 2003 Elsevier Ltd. All rights reserved.