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 one "ectopia" is present in each affected brain. Studies in other mouse strains have shown that these ectopias occur before birth, probably because of a breach in the superficial glial membrane during neuronal migration. The ectopias are heritable and are caused by multiple genes. C57BL/6J mice exposed prenatally to acetazolamide, a carbonic anhydrase-specific inhibitor and teratogen, develop an increased frequency of limb malformations, especially in the right forelimb. In the present study, we hypothesized that the prevalence and severity of ectopias would be increased in acetazolamide-exposed mice because carbonic anhydrase plays a key role in brain development. Further, we wanted to determine whether there was a correlation between the side of limb deformity and the hemisphere containing an ectopia. Thus, we injected C57BL/6J time-mated mice intraperitoneally on embryonic day 9 with either sodium acetazolamide (750 mg/kg) or water. Histological analysis of the brains from 105 acetazolamide-exposed offspring and 89 control offspring revealed no difference in the overall prevalence of cerebrocortical ectopias between the acetazolamide and control groups: 34% of the acetazolamide-exposed and 28% of the control mice had ectopias. There was, however, a striking 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 ectopias in some mouse strains, but epigenetic factors such as prenatal exposure to acetazolamide can influence their severity.
Sherman
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GF
Dyslexia Research Laboratory, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Holmes
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LB
D000086:Acetazolamide / Q000633:toxicity*; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000633:toxicity*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013723:Teratogens / Q000633:toxicity
D002257:Carbonic Anhydrase Inhibitors; D013723:Teratogens; D000086:Acetazolamide