Characterization of neuronal migration disorders in neocortical structures .1. Expression of epileptiform activity in an animal model

Hypoxia, ischemia and other forms of brain injury during the pre- or perinatal period may cause neuronal migration disorders which result in irreversible structural modifications. In human neocortex, these malformations have been associated with severe mental retardation, motor dysfunction and the manifestation of therapy-resistant epilepsy. We were interested in analyzing the expression of epileptiform activity in an animal model of neocortical migration disorders. Newborn rats received a focal cortical freeze lesion and were investigated anatomically and in vitro electrophysiologically after survival times of up to five months. Anatomic abnormalities included loss of normal cortical lamination (focal microgyrus) and presence of ectopic cell clusters in layer I and in the white matter (heterotopia). The functional in vitro analyses with eight extracellular recording electrodes revealed a prominent hyperexcitability of the disorganized neocortical network. Electrical stimulation of the afferents elicited epileptiform responses that propagated over >4 mm in the horizontal direction. In untreated and sham-operated animals, this spread of evoked activity was restricted to 0.5-1 mm. Epileptiform responses were not significantly affected by APV but blocked by NBQX, indicating that AMPA receptors play a prominent role in the generation and propagation of this pathophysiological activity. Our data suggest that the experimentally induced migration disturbances cause long-term structural and/or functional modifications in the neocortical network which may form the basis for the expression of epileptiform activity.