The GABAergic system has long been implicated in
epilepsy with defects in
GABA neurotransmission being linked to
epilepsy in both experimental animal models and human syndromes (Olsen and Avoli, 1997). However, to date no human
epileptic syndrome has been directly attributed to an altered GABAergic system. The observed defects in
GABA neurotransmission in human
epileptic syndromes may be the indirect result of a brain besieged by
seizures. The use of animal models of
epilepsy has sought to address these matters. The advent of gene targeting methodologies in mice now allows for a more direct assessment of
GABA's involvement in epileptogenesis. To date several genes associated with the GABAergic system have been disrupted. These include the genes for
glutamic acid decarboxylase, both the 65- and 67-kDa
isoforms (GAD65 and GAD67), the tissue non-specific
alkaline phosphatase gene (TNAP) and genes for the
GABA(A) receptor subunits alpha6, beta3, gamma2, and delta (gabra6, gabrb3, gabrg2, and gabrd respectively). Gene disruptions of either GAD67 or gabrg2 result in neonatal lethality, while others, GAD65, TNAP, and gabrb3 exhibit increased mortality and spontaneous
seizures.
GABA receptor expression has been found to be both regionally and developmentally regulated. Thus in addition to their obvious role in controlling excitability 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 beta3 subunit gene, gabrb3/GABRB3 (mouse/human), is of particular interest because of its expression early in development and its possible role in the
neurodevelopmental disorder Angelman syndrome. Individuals with this syndrome exhibit severe
mental retardation and
epilepsy. Mice with the gabrb3 gene disrupted likewise exhibit electroencephalograph (EEG) abnormalities,
seizures, and behavioral characteristics typically associated with
Angelman syndrome. These gabrb3 gene knockout 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.