GABAA receptor beta3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in beta3 subunit levels, EEG, and behavior.
The homozygous knockout mouse for the beta3 subunit of the GABAA receptor has been proposed as a model for the neurodevelopmental disorder, Angelman syndrome, based on phenotypic similarities of craniofacial abnormalities, cognitive defects, hyperactivity, motor incoordination, disturbed rest-activity cycles, and epilepsy. Since most children with Angelman syndrome are autosomal heterozygotes of maternal origin, apparently through genomic imprinting, we used gabrb3-deficient heterozygote mice of defined parental origin to investigate whether this phenotype is also maternally imprinted in mouse. Whole brain extracts showed greatly reduced beta3 subunit levels in male mice of maternal origin but not in male mice of paternal origin. Females of both parental origin showed greatly reduced beta3 subunit levels. Heterozygotes did not exhibit hyperactive circling behavior, convulsions, or electrographically recorded seizures. EEGs showed qualitative differences among heterozygotes, with male mice of maternal origin demonstrating more abnormalities including increased theta activity. Ethosuximide inhibited theta bursts, suggesting an alteration in the thalamocortical relay. Carbamazepine induced EEG slowing in males and EEG acceleration in females, with a larger effect in paternal-origin heterozygotes. Evidence thus suggests both parent-of-origin and gender-related components in developmental regulation of beta3 expression, in particular, that the maternally-derived male heterozygote may carry a developmental modification resulting in less beta3 protein, which may reflect partial genomic imprinting of the gabrb3 gene in mice.
Liljelund
Patricia
P
Brain Research Institute and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Handforth
Adrian
A
Homanics
Gregg E
GE
Olsen
Richard W
RW
D017204:Angelman Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D006579:Heterozygote; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000235:genetics*; D012640:Seizures / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; C546270:Gabrb3 protein, mouse; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid