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pubmed:abstractText |
Knock-in mice were constructed with mutations in the ?1 (H(270), A(277)) and ?2 (H(270), A(277)) subunits of the GABAA receptor, which resulted in receptors that lacked modulation by ethanol but retained normal responses to GABA in vitro. A key question is whether these mutant receptors also function normally in vivo. Perturbation of brain function was evaluated by gene expression profiling in the cerebral cortex and by behavioral pharmacology experiments with GABAergic drugs. Analysis of individual transcripts found only six transcripts that were changed in ?1 knock-in mice and three in the ?2 mutants (p<0.05, corrected for multiple comparisons). Two transcripts that are sensitive to neuronal activity, Arc and Fos, increased about 250% in the ?2 mutants, and about 50% in the ?1 mutants. Behavioral effects (loss of righting reflex, rotarod) of flurazepam and pentobarbital were not different between ?2 mutants and wild-type, but they were enhanced for ?1 knock-in mice. These results indicate that introduction of these mutations in the ?2 subunit of the GABAA receptor does not produce marked perturbation of brain function, as measured by gene expression and GABAergic behavioral responses, but the same mutations in the ?1 subunit produce more pronounced changes, especially in GABAergic function.
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pubmed:affiliation |
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, 1 University Station, A4800, Austin, TX 78712, United States.
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