Embryonic exposure to ethanol disturbs regulation of mitotic spindle orientation via GABAA receptors in neural progenitors in ventricular zone of developing neocortex

Abstract

Neural progenitors in the ventricular zone of the developing neocortex divide oriented either parallel or perpendicular to the ventricular surface based on their mitotic spindle orientation. It has been shown that the cleavage plane orientation is developmentally regulated and plays a crucial role in cell fate determination of neural progenitors or the maintenance of the proliferative ventricular zone during neocortical development. We tested if fetal exposure to ethanol, the most widely used psychoactive agent and a potent teratogen that may cause malformation in the central nervous system, alters mitotic cleavage orientation of the neural progenitors at the apical surface of the ventricular zone in the developing neocortex. Fetal exposure to ethanol on E10.5 and 11.5 increased the occurrence frequency of a horizontal cleavage plane that is parallel to the ventricular surface on E 12.5. Administration of picrotoxin, a GABA(A) receptor antagonist, prior to ethanol administration canceled the effect of ethanol with the frequency of horizontal division similar to the control level, although picrotoxin itself did not show any effect on cleavage plane orientation. Phenobarbital, a GABA(A) receptor agonist, induced horizontal cleavage to an extent similar to that induced by ethanol administration. (+)MK801, an antagonist of NMDA receptor that is another major target of ethanol in neural cells, did not affect the cleavage plane of dividing progenitors. These results suggest that fetal ethanol exposure induced alterations in the cleavage plane orientation of neural progenitors in the ventricular zone of the neocortex via the enhancement of the function of GABA(A) receptors.