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 p erinatal period may cause neuronal migration disorders which result in irreversible structural modifications. In human neocortex, these malf ormations have been associated with severe mental retardation, motor d ysfunction and the manifestation of therapy-resistant epilepsy. We wer e interested in analyzing the expression of epileptiform activity in a n animal model of neocortical migration disorders. Newborn rats receiv ed a focal cortical freeze lesion and were investigated anatomically a nd in vitro electrophysiologically after survival times of up to five months. Anatomic abnormalities included loss of normal cortical lamina tion (focal microgyrus) and presence of ectopic cell clusters in layer I and in the white matter (heterotopia). The functional in vitro anal yses with eight extracellular recording electrodes revealed a prominen t hyperexcitability of the disorganized neocortical network. Electrica l stimulation of the afferents elicited epileptiform responses that pr opagated 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 r ole in the generation and propagation of this pathophysiological activ ity. Our data suggest that the experimentally induced migration distur bances cause long-term structural and/or functional modifications in t he neocortical network which may form the basis for the expression of epileptiform activity.