Screening for the effects of antiepileptic drugs on short term plasticity using a time efficient bioassay

Screening for changes in the short-term plasticity (STP) characteristics induced by antiepileptic drugs (AEDs) can be accelerated using a novel in vitro bioassay. The bioassay is based on the analysis of varying population spike (PS) amplitudes recorded in the CA1 region of the hippocampal slice in response to Poisson distributed random electrical stimuli. Three antiepileptic drugs (phenytoin 100 microM, carbamazepine 100 microM, and valproate 700 microM) were tested at maximal effective therapeutic concentrations. The data were analyzed using an advanced nonlinear approach that is more specific and time-efficient than the conventional paired pulse and fixed frequency train methods. STP was quantified by the first and the second order Volterra kernels. The first order kernel (k1) represented the mean PS amplitude while the second order kernel (k2) quantified the effect on the current PS amplitude of the interaction between the current stimulus impulse and each past stimulus impulse within a time (memory) window mu. The mean PS (k1 decreased by 15%, 10%, and 7% when phenytoin, carbamazepine, and valproate were added respectively. Phenytoin caused an increase in the k2 peak facilitation in the high frequency domain. Carbamazepine impaired frequency facilitation in the theta frequency range by causing a left shift in the second order kernel.