MICE LACKING THE BETA(3) SUBUNIT OF THE GABA(A) RECEPTOR HAVE THE EPILEPSY PHENOTYPE AND MANY OF THE BEHAVIORAL-CHARACTERISTICS OF ANGELMAN-SYNDROME

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulti ng from a deletion/mutation in maternal chromosome 15q11-13. The genes in 15q11-13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduct ion in the GABA(A) receptor beta(3) subunit (GABRB3) gene, contained w ithin the AS deletion region, may contribute to the overall severity o f AS. Disrupting the gabrb3 gene in mice produces electroencephalograp hic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacologi cal response profile to antiepileptic medications similar to that obse rved in AS. Additionally, these mice exhibited learning and memory def icits, poor motor skills on a repetitive task, hyperactivity, and a di sturbed rest-activity cycle, features all common to AS. The loss of th e single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans proba bly contributes to the overall phenotype of Angelman syndrome. At leas t one other gene, the EG-associated protein ubiquitin-protein ligase ( UBE3A) gene, has been implicated in AS, so the relative contribution o f the GABRB3 gene alone or in combination with other genes remains to be established.