Int. J. Devl Neuroscience 22 (2004) 137–147 Perinatal exposure to GABA-transaminase inhibitor impaired psychomotor function in the developing and adult mouse T. Levav, T. Saar, L. Berkovich, H. Golan ∗ Department of Developmental Molecular Genetics, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel Received 23 February 2004; received in revised form 16 March 2004; accepted 17 March 2004 Abstract Antiepileptic drugs acting through the potentiation of GABA-ergic pathways have harmful effects on brain development. Increased risk of impaired intellectual development was reported in children born to women treated for epilepsy during pregnancy. Here we examined the vulnerability of the developing brain to treatment with one of the new antiepileptic drugs—vigabatrin—during two time periods in newborn mice (postnatal days 1–7 and 4–14) which parallel the third trimester of human embryo brain development. Delayed development of sensory and motor reflexes, reduced mobility in the open field, impaired object recognition and deficient spatial learning and memory were observed independently of the treatment period. On the contrary, specific susceptibility to the age of exposure was detected in various motor functions. A number of morphological correlates may explain these behavioral alterations; a transient increase in CA1 pyramidal cell layer (P< 0.001) and decrease in granular cell layer (P< 0.05) in hippocampus were detected at postnatal day 7. In addition, a significantly lower cell density was observed in the adult mouse brain in all layers of the M2 cerebral cortex of mice treated during days 4–14, compared to the controls (P< 0.05). Our findings demonstrated short- and long-term deleterious effects of vigabatrin treatment and suggest a specific vulnerability of the developing motor system to GABA enhancement during the first postnatal week. © 2004 ISDN. Published by Elsevier Ltd. All rights reserved. Keywords: Antiepileptic drugs; GABA; Hippocampus; Learning; Memory; Morphogenesis 1. Introduction Antiepileptic drugs acting through the potentiation of GABA-ergic pathways may have detrimental effects on brain development. Indeed, the increased risk of delayed psychomotor development was described in the earliest re- ports of the teratogenic effects of antiepileptic drugs (AEDs) (Meadow, 1968; Hanson et al., 1976). Since then, several studies have reported impaired psychomotor development in children born to women treated for epilepsy during pregnancy (Hansen and Lou, 2000). Long-term studies in children exposed to AEDs before birth have demonstrated adverse neurodevelopmental outcomes in 19% of infants, as compared to 3% of control siblings (Dean et al., 2002). In follow-up studies of preschool children, it has been found that AEDs and phenytoin are associated with a decrease in intelligence quotient (IQ) and specific cognitive dys- functioning (Scolnick et al., 1994). A follow-up study of children in the 6–13 age group showed a connection be- ∗ Corresponding author. Tel.: +972-8-647-9974; fax: +972-8-627-6215. E-mail address: havag@bgumail.bgu.ac.il (H. Golan). tween prenatal Phenobarbital, a small head circumference and poorer cognitive performance (Van der Pol et al., 1991). Adults exposed prenatally to phenobarbital and pheny- toin have also been shown to have a significantly smaller head circumference at birth, significantly increased learn- ing problems and mental retardation in adulthood (Dessens et al., 2000). Antiepileptic drugs have also been shown to be deleterious to neurodevelopmental outcomes when given during infancy. Prolonged treatment with phenobarbital in infants with febrile seizures has been shown to impair cognitive development (Volpe, 2001). Recent studies in animal models on the effects of short and prolonged exposure to AEDs on the developing brain indicate that modulation of GABA may play an important role in the pathogenesis of brain injury associated with these agents. Vigabatrin (VGB), which inhibits GABA degrada- tion by blocking the enzyme GABA-transaminase, increases the concentration of GABA in the brain (Qume et al., 1995). Treatment with VGB in newborn rats (P14–P26) caused marked white matter damage and resulted in behav- ioral hyperactivity. Remarkably, after a 2-week recovery period, most of the histological damage had resolved, while 0736-5748/$30.00 © 2004 ISDN. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijdevneu.2004.03.004