Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior

Abstract

ABSTRACT␥-Aminobutyric acid type A receptors (GABA A -Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The ␤3 subunit is an essential component of the GABA A -R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a ␤3 gene inactivated by gene targeting. GABA A -R density is approximately halved in brain of ␤3-deficient mice, and GABA A -R function is severely impaired. Most ␤3-deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. ␤3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the ␤3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. ␤3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and͞or pleiotropic developmental defects.

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

“…High doses of ethanol (2 g kg −1 ) have been reported to similarly impair wild-type and Gabra6 −/− mice in rotarod tests 40 , and at ethanol doses of 3.5 g kg −1 , no significant differences have been observed between wild type and Gabra6 −/− in a LORR test 41,42 . At such high ethanol doses, we also find no change for Gabra6 100R/100R and Gabra6 100Q/100Q rats in rotarod performance (data not shown) or in LORR (Fig 5e,f).…”

Advances in behavioral genetics: mouse models of autism

“…91 Surviving offspring evidence many markers for neuropathology, including enhanced seizure susceptibility, abnormal motor coordination, hyperactivity and stereotyped circling behavior, and impaired learning and memory. 91,92 PWS, arising from the paternal deficiency of an imprinted region on 15q11-13 different from that associated with AS, is characterized by mental retardation, early-onset obesity and autistic-like repetitive behavior, including compulsions, rituals, and resistance to environmental change. 93 Unfortunately, mouse models for the multigene deletion associated with PWS have shown early postnatal lethality.…”

GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5

“…Well-documented is the indispensable role of the GABA signaling in the morphogenesis of the embryonic palate (Culiat et al, 1995;Asada et al, 1997;Condie et al, 1997;Homanics et al, 1997;Ji et al, 1999;Hagiwara et al, 2003), although the underlying molecular mechanism is still unknown.…”