GABAA Receptor 1 Subunit (Gabra1) Knockout Mice: Review and New Results

The inhibitory GABA_A receptor plays important roles in the control of anxiety and sleep behavior. The α1 subunit-containing GABA_A receptor is the major subtype, contributing to about 60% of all GABA_A receptors in the brain. In this chapter, we present phenotypes observed in a GABA_A receptor alpha-1 subunit (Gabra1) knockout line (KO). Our results are reviewed along with those from earlier publications on different Gabra1 mutant lines. We discovered a heightened anxiety profile in KO mice in several behavioral assays. Gabra1 KO mice were found to bury fewer marbles in a novelty-induced digging test, spent less time in the brightly lit area in the platform test, spent decreased time in the central area of the open field, and also had increased auditory startle responses. Increased anxiety behavior was especially evident using the platform and marble-burying assays. Contrary to the results in these assays of unconditioned anxiety, Gabra1 KO did not differ in acquiring fear-potentiated startle. Continuous electroencephalogram (EEG) recording is reported for the first time here. KO mice spent significantly more time in nonrapid eye movement (NREM) sleep, and significantly less time in rapid eye movement (REM) sleep and in waking during both light and dark periods. KO mice also exhibited significantly increased power in frequencies above 12 Hz in all vigilance states, suppressed power in slow waves (0.5-4 Hz) during NREM sleep and waking, and a left-shifted peak frequency of theta activity in REM sleep. Overall, the phenotypic assessments of Gabra1 knockout mice from all reports are very similar. However, the platform and marble-burying tests appear to be especially useful in detecting changes in anxiety. Taken together, the results of these studies confirm the essential roles of the Gabra1 subunit in neural and pharmacological modulation of sedation, anxiety, and sleep and support the use of KO mice to predict the therapeutic potential of novel targets.