Long-Term Antiepileptic Drug Administration During Early Life Inhibits Hippocampal Neurogenesis in the Developing Brain

Certain antiepileptic drugs (AEDs) that are commonly used to treat seizures in children also affect cognition, and these effects can persist into adulthood, long after drug withdrawal. Widespread enhancement of apoptosis may be one mechanism underlying these lasting cognitive changes. Whether AEDs affect other processes in brain development during early postnatal life has not, however, been systematically analyzed. Here we determined whether chronic administration of common AEDs during early life alters cell proliferation and neurogenesis in the hippocampus. Postnatal day 7 (P7) rats received phenobarbital, clonazepam, carbamazepine, valproate, topiramate, or vehicle for 28 days. Bromodeoxyuridine was administered on P34 to label dividing cells. Cell proliferation was assessed 24 hr later, and cell survival and differentiation were assessed 28 days later. Phenobarbital and clonazepam significantly inhibited cell proliferation by 63% and 59%, respectively, and doublecortin immunoreactivity (indicator of neurogenesis) in the dorsal hippocampus was also significantly decreased by 26% and 24%, respectively. Survival of new cells steadily decreased in phenobarbital and clonazepam groups over 28 days. Reduced cell proliferation and survival resulted in fewer new neurons in the dentate gyrus, as confirmed by neuronal counting on P62. There were, however, no differences in cell distribution pattern or differentiation toward neuron and glial cells when phenobarbital and clonazepam groups were compared with controls. There were no changes in rats exposed to carbamazepine, valproate, or topiramate. Thus, inhibiting cell proliferation, survival, and neurogenesis in the developing hippocampus may be another potential mechanism underlying brain impairment associated with certain AED therapies in early life. (C) 2009 Wiley-Liss, Inc.