VALPROATE AND SODIUM CURRENTS IN CULTURED HIPPOCAMPAL-NEURONS

Cultured rat hippocampal neurons with short processes were investigated using the whole cell voltage clamp under conditions appropriate for isolating Na+ currents. After incubation of the neuron culture for a period of 15-30 min in 1 mM sodium valproate, several parameters of the Na+ current were changed. The peak Na+ conductance g(p), measured using hyperpolarizing prepulses, was reduced by valproate in a voltage-dependent manner. In the membrane voltage range from -30 to +20 mV, this reduction showed a linear dependence on voltage, increasing from about zero to approximately 30% of g(p)BAR, the maximum peak Na+ conductance of the neuron. At the holding voltage of -70 mV, the inactivation parameter h(infinity) decreased from 0.88 in the control to 0.64 in the valproate solution. This reduction originated mainly from a 10 mV shift in the sigmoid relation between h(infinity) and membrane voltage along the voltage axis to hyperpolarizing potentials. The decay of the maximum peak Na+ current (inactivation) could be fitted by a biexponential function. Time constants of the fast and slow component at -20 mV decreased in valproate by about 50%. Valproate also retarded the recovery from inactivation, as determined at the holding voltage. The sigmoid recovery from inactivation could reasonably be described by an exponential function with time constant tau(r) and delay time DELTAt. Both tau(r) and DELTAt increased more than 200% in valproate. Our results indicate that valproate affected the Na+ current in hippocampal neurons in a way that contributed to a considerable depression of Na+ reactivation. This explains the frequency-dependent inhibition of action potentials as observed in mammalian central nervous tissue and may be the principal action of the anticonvulsant.