CELLULAR AND MOLECULAR CHANGES LEADING TO NEOCORTICAL HYPEREXCITABILITY IN ANIMAL MODELS OF ABSENCE EPILEPSY

The cortex and thalamus generate brain rhythms such as EEG spindles during drowsiness or sleep, and contribute to spike and wave (SW) discharges that are associated with absence seizures in patients with genetic, primary generalized epilepsies. Here, we will summarize electrophysiological and molecular data obtained in animal models that mimic this neurological disorder. In particular, we will focus on thalamocortical synchronization, which is altered in genetic rodent models of absence seizures such as the GAERS and the WAG/Rij. Moreover, as reported in humans, the WAG/Rij rat neocortex plays a crucial role in SW discharge generation. Indeed, findings obtained to date suggest that: (i) hyperexcitable neocortical cells in epileptic rats make thalamic reticular nucleus neurons fire action potential bursts, which are more intense than in non-epileptic control (NEC) animals; (ii) these enhanced bursts cause extended IPSPs in thalamic relay cells that reduce the pacing frequency of thalamocortical volleys; (iii) this decrease in frequency results in recruitment of a larger number of cortical and thalamic neurons causing amplification of the oscillations, and hence SW appearance.

When compared with age-matched NEC, neocortical cells in epileptic WAG/Rij rats have: (i) increased, NMDA receptor-mediated synaptic excitability; and (ii) almost comparable stimulus-induced, GABA receptor-mediated IPSPs. We have also identified decreased paired-pulse depression of both excitatory and inhibitory potentials in the epileptic WAG/Rij rat neocortex; such a process is largely contributed by the activation of presynaptic GABAB receptors. Finally, we have discovered with real-time RT-PCR that these functional data correlate with a reduced expression in the epileptic WAG/Rij neocortex of mRNAs encoding specific GABAB receptor subunits. This evidence suggests that a diminished function of presynaptic GABAB receptors makes epileptic WAG/Rij neocortical networks hyperexcitable by increasing inhibitory and, perhaps to an even greater extent, excitatory transmitter release. We anticipate that these data will be relevant for understanding the etiology of human absence seizures.