Testing the silence of mutations: Transcriptomic and behavioral studies of GABAA receptor α1 and α2 subunit knock-in mice

Knock-in mice were constructed with mutations in the alpha 1 (H-270, A(277)) and alpha 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 alpha 1 knock-in mice and three in the alpha 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 alpha 2 mutants, and about 50% in the alpha 1 mutants. Behavioral effects (loss of righting reflex, rotarod) of flurazepam and pentobarbital were not different between alpha 2 mutants and wild-type, but they were enhanced for alpha 1 knock-in mice. These results indicate that introduction of these mutations in the alpha 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 alpha 1 subunit produce more pronounced changes, especially in GABAergic function. (C) 2010 Elsevier Ireland Ltd. All rights reserved.