ELECTROPHYSIOLOGIC ANALYSIS OF THE ACTIONS OF VALPROATE ON PYRAMIDAL NEURONS IN THE RAT HIPPOCAMPAL SLICE

Purpose: Studies in invertebrates and cultured mammalian neurons sugge sted that valproate (VPA) mediates its main antiepileptic effect by sl owing the recovery from inactivation of voltage-dependent sodium chann els. This predicts an effect on the refractory period of the action po tential and. consequently, on the bursting behavior of neurons. Method s: We investigated this prediction using intracellular and extracellul ar recording techniques in hippocampal slices prepared from adult rats . The refractory period (RFP) and the ratio of the slopes (SR) of a pa ir of action potentials were used as indices of the recovery from inac tivation of sodium channels, They were measured by injecting a series of paired depolarizing current pulses into CA1 pyramidal neurons. Resu lts: No significant changes were observed in the RFP or SR measured du ring a 1-h recording period when VPA vias bath-applied (1 mM), or when it was present in the recording electrode (10-50 mM). Lowering the te mperature from 34.5 degrees C to 26.4 degrees C resulted in an increas e of the RFP by 100% and a decrease of tile SR by 40%. However, VPA di d not affect any of the measured action potential parameters at this l ower temperature. VPA was also without effect on the presynaptic fiber volley of axons recorded extracellularly in the stratum radiatum. The antidromic population spike was unaffected by VPA (2 mM), whereas phe nytoin (50 mu M) clearly affected this spike in the same slices. The a bsence of effect of VPA on each of the measured parameters could not b e attributed to poor penetration through the slice because bath-applie d VPA reduced the frequency of extracellularly recorded spontaneous in terictal bursts, induced by bicuculline and elevated K+, within 10 min . Conclusions: These findings suggest that at least in the hippocampal slice the drug's principal antiepileptic effect cannot be explained b y its action on voltage-dependent sodium channels.