Perinatal exposure to GABA-transaminase inhibitor impaired psychomotor function in the developing and adult mouse.
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.
Levav
T
T
Department of Developmental Molecular Genetics, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
Saar
T
T
Berkovich
L
L
Golan
H
H
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000009:adverse effects*; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011596:Psychomotor Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000196:embryology / Q000473:pathology*; D011597:Psychomotor Performance / Q000187:drug effects*; D020888:Vigabatrin / Q000009:adverse effects*
D000927:Anticonvulsants; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin