GABAergic synaptic inhibition is reduced before seizure onset in a genetic model of cortical malformation.

Abstract

Malformations of the neocortex are a common cause of human epilepsy; however, the critical issue of how disturbances in cortical organization render neurons epileptogenic remains controversial. The present study addressed this issue by studying inhibitory structure and function before seizure onset in the telencephalic internal structural heterotopia (tish) rat, which is a genetic model of heightened seizure susceptibility associated with a prominent neocortical malformation. Both normally positioned (normotopic) and misplaced (heterotopic) pyramidal neurons in the tish neocortex exhibited lower resting membrane potentials and a tendency toward higher input resistance compared with pyramidal neurons from control brains. GABAergic synaptic transmission was attenuated in the tish cortex, characterized by significant reductions in the frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs recorded from pyramidal neurons. In addition, the amplitudes of sIPSCs were reduced in the tish neocortex, an effect that was more profound in the normotopic cells. Immunohistochemical assessment of presynaptic GABAergic terminals showed a reduction in terminals surrounding pyramidal cell somata in normotopic and heterotopic tish neocortex. The attenuation of inhibitory innervation was more prominent for normotopic neurons and was associated with a reduction in a subset of GABAergic interneurons expressing the calcium-binding protein parvalbumin. Together, these findings indicate that key facets of inhibitory GABAergic neurotransmission are disturbed before seizure onset in a brain predisposed to developing seizures. Such alterations represent a rational substrate for reduced seizure thresholds associated with certain cortical malformations.