Cerebrocortical microdysgenesis is enhanced in C57BL/6J mice exposed in utero to acetazolamide

A small percentage of C57BL/6 mice spontaneously develop focal collections of neurons in the molecular layer of the cerebral neocortex. Usually only o ne "ectopia" is present in each affected brain. Studies in other mouse stra ins have shown that these ectopias occur before birth, probably because of a breach in the superficial glial membrane during neuronal migration. The e ctopias are heritable and are caused by multiple genes. C57BL/6J mice expos ed prenatally to acetazolamide, a carbonic anhydrase-specific inhibitor and teratogen, develop an increased frequency of limb malformations, especiall y in the right forelimb. In the present study, we hypothesized that the pre valence and severity of ectopias would be increased in acetazolamide-expose d mice because carbonic anhydrase plays a key role in brain development. Fu rther, we wanted to determine whether there was a correlation between the s ide of limb deformity and the hemisphere containing an ectopia. Thus, we in jected C57BL/6J time-mated mice intraperitoneally on embryonic day 9 with e ither sodium acetazolamide (750 mg/kg) or water. Histological analysis of t he brains from 105 acetazolamide-exposed offspring and 89 control offspring revealed no difference in the overall prevalence of cerebrocortical ectopi as between the acetazolamide and control groups: 34% of the acetazolamide-e xposed and 28% of the control mice had ectopias. There was, however, a stri king difference in the shape and size of ectopias: 67% of the ectopias were large in the acetazolamide-exposed group in comparison to 32% in controls. The acetazolamide-exposed offspring also were more likely to have multiple ectopias. Thus, there may be a genetic predisposition for developing ectop ias in some mouse strains, but epigenetic factors such as prenatal exposure to acetazolamide can influence their severity. Teratology 60:137-142, 1999 . (C) 1999 Wiley-Liss, Inc.