Effects of sodium valproate on synaptic transmission and neuronal excitability in rat hippocampus

1. Valproate (VPA) has long been used in the treatment of both generalized and partial seizures. However, its cellular mechanisms of action remain unclear. 2. In the present study, the effects of VPA on synaptic transmission and neuronal excitability were examined in the hippocampal CA1 region using whole-cell patch clamp recordings. 3. Perfusion with VPA, at therapeutically attainable concentrations (i.e. 0.3 and 0.6 mmol/L), significantly increased the frequency (112 +/- 2 and 133 +/- 2% of control, respectively; n = 5; both P < 0.05), but not the average amplitude, of miniature inhibitory post-synaptic currents (mIPSCs). Perfusion with VPA had no effect on either the amplitude or the frequency of miniature excitatory post-synaptic currents (mEPSCs). 4. In acutely dissociated CA1 pyramidal neurons, VPA had no effect on 10 micromol/L GABA-induced currents. Furthermore, following the administration of 0.3 and 0.6 mmol/L VPA, the frequency of action potential firing was significantly reduced from 18.0 +/- 1.1 to 15.3 +/- 0.9 and from 18.6 +/- 0.9 to 12.6 +/- 0.6, respectively (n = 8; both P < 0.05). In contrast, 0.3 and 0.6 mmol/L VPA significantly increased spike frequency adaptation from 4.02 +/- 0.47 to 4.72 +/- 0.55 and from 3.47 +/- 0.41 to 4.48 +/- 0.58, respectively (n = 8; P < 0.05). 5. The results of the present study suggest that VPA presynaptically increases inhibitory synaptic activity without modifying excitatory synaptic transmission and reduces neuronal excitability. Any or all of these effects may contribute to its anticonvulsant action.