Altered Migratory Behavior of Interneurons in a Model of Cortical Dysplasia: The Influence of Elevated GABAA Activity

Abstract

Appropriate function of the neocortex depends on timely generation and migration of cells produced in the germinal zones of the neocortex and ganglionic eminence (GE). Failure to accurately complete migration results in cortical dysplasia, a developmental syndrome implicated in many neurologic disorders. We developed a model of cortical dysplasia in ferrets involving administration of methylaxozymethanol acetate (MAM), an antimitotic, to pregnant ferrets on gestational day 33, leading to dramatic reduction of layer 4 in the neocortex. Here, using time-lapse video imaging, we investigate dynamic behavior of migrating cells arising from the GE and cortical ventricular zone (CVZ) in ferrets and the role of GABAA activity. Treatment with MAM significantly reduced migration speed and the relative proportion of cells arising from the GE demonstrating exploratory behavior. To a lesser extent, the behavior of cells leaving the CVZ was affected. Pharmacologic inhibition of GABAA receptors (GABAAR) improved the speed of migration and exploratory ability of migrating MAM-treated cells arising from the GE. Additionally, the expression of α2 and α3 subunits of GABAAR and the potassium chloride co-transporter (KCC2) increased in the neocortex of MAM-treated animals. After MAM treatment, increases in endogenous KCC2 and GABAAR combine to alter the dynamic properties and exploratory behavior of migrating interneurons in ferrets. We show a direct correlation between increased GABAA and KCC2 expression with impaired migration and ability to explore the environment.