Mechanisms underlying epileptogenesis in cortical malformations

The presence of developmental cortical malformations is associated with epi leptogenesis and other neurological disorders. In recent years, animal mode ls specific to certain malformations have been developed to study the under lying epileptogenic mechanisms. Teratogens (chemical, thermal or radiation) applied during cortical neuroblast division and migration result in lissen cephaly and focal cortical dysplasia. Animals with these malformations have a lowered seizure threshold as well as histopathologies typical of those f ound in human dysgenic brains. Alterations that may promote epileptogenesis have been identified in lissencephalic brains, such as increased numbers o f bursting types of neurons, and abnormal connections between hippocampus, subcortical heterotopia, and neocortex. A distinct set of pathological prop erties is present in animal models of 4-layered microgyria, induced with co rtical lesions made during late stages of cortical neuroblast migration. Hy perexcitability has been demonstrated in cortex adjacent to the microgyrus (paramicrogyral zone) in in vitro slice preparations. A number of observati ons suggest that cellular differentiation is delayed in microgyric brains. Other studies show increases in postsynaptic glutamate receptors and decrea ses in GABA(A) receptors in microgyric cortex. These alterations could prom ote epileptogenesis, depending on which cell types have the altered recepto rs. The microgyrus lacks thalamic afferents from sensory relay nuclei, that instead appear to project to the paramicrogyral region, thereby increasing excitatory connectivity within this epileptogenic zone. These studies have provided a necessary first step in understanding molecular and cellular me chanisms of epileptogenesis associated with cortical malformations. (C) 199 9 Elsevier Science B.V. All rights reserved.