GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man

The GABAergic system has long been implicated in epilepsy with defects in G ABA neurotransmission being linked to epilepsy in both experimental animal models and human syndromes (Olsen and Avoli, 1997). However, to date no hum an epileptic syndrome has been directly attributed to an altered GABAergic system. The observed defects in GABA neurotransmission in human epileptic s yndromes may be the indirect result of a brain besieged by seizures. The us e of animal models of epilepsy has sought to address these matters. The adv ent of gene targeting methodologies in mice now allows for a more direct as sessment of GABA's involvement in epileptogenesis. To date several genes as sociated with the GABAergic system have been disrupted. These include the g enes for glutamic acid decarboxylase, both the 65- and 67-kDa isoforms (GAD 65 and GAD67), the tissue non-specific alkaline phosphatase gene (TNAP) and genes for the GABA receptor subunits alpha(6), beta(3), gamma(2), and delt a (gabra6, gabrb3, gabrg2, and gabrd respectively). Gene disruptions of eit her GAD67 or gabrg2 result in neonatal lethality, while others, GAD65, TNAP , and gabrb3 exhibit increased mortality and spontaneous seizures. GABA rec eptor expression has been found to be both regionally and developmentally r egulated. Thus in addition to their obvious role in controlling excitabilit y in adult brain, a deficit in GABAergic function during development could be expected to elicit pleiotropic neurodevelopmental abnormalities perhaps including epilepsy. The GABA(A) receptor beta(3) subunit gene, gabrb3/GABRB 3 (mouse/human), is of particular interest because of its expression early in development and its possible role in the neurodevelopmental disorder Ang elman syndrome. Individuals with this syndrome exhibit severe mental retard ation and epilepsy. Mice with the gabrb3 gene disrupted likewise exhibit el ectroencephalograph (EEG) abnormalities, seizures, and behavioral character istics typically associated with Angelman syndrome. These gabrb3 gene knock out mice provide direct evidence that a reduction of a specific subunit of the GABA(A) receptor system can result in epilepsy and support a GABAergic role in the pathophysiology of Angelman syndrome. (C) 1999 Elsevier Science B.V. All rights reserved.