Alteration of Interneuron Migration in a Ferret Model of Cortical Dysplasia

Abstract

During cerebral cortical development, gamma-aminobutyric acidergic (GABAergic) interneurons arise from a different site than projection neurons. GABAergic cells are generated in the subpallial ganglionic eminence (GE), while excitatory projection neurons arise from the neocortical ventricular zone. Our laboratory studies a model of cortical dysplasia that displays specific disruption of GABAergic mechanisms and an alteration in the overall balance of excitation in the neocortex. To produce this model, the birth of neurons on a specific gestational day in ferrets (embryonic day 33 [E33]) is interrupted by injection of the antimitotic methylazoxymethanol (MAM). We hypothesized that migration of interneurons might be disrupted in this cortical dysplasia paradigm. We observed that although interneurons migrate into the neocortex in both normal and dysplastic cortex, the migrating cells become disoriented over time after E33 MAM treatment. Coculture experiments using normal GE and MAM-treated cortex (and vice versa) demonstrate that cues dictating proper orientation of migrating interneurons arise from the cortex and are not intrinsic to the migrating cells. As a consequence, interneurons in mature brains of MAM-treated animals are abnormally distributed. We report that GABA(A) receptor activation is crucial to the proper positioning of interneurons migrating into the cortex from the GE in normal and MAM-treated animals.