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5 subunit deficient mice
1 Neurology, UCLA School of Medicine, Los Angeles, CA, USA; Neuroscience IDP, UCLA School of Medicine, Los Angeles, CA, USA
2 Neurology, UCLA School of Medicine, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: mody{at}ucla.edu.
Functionally, GABAA receptor (GABAR)-mediated inhibition can be classified as phasic (synaptic) and tonic (extrasynaptic). The GABARs underlying tonic inhibition assemble from different subunits than those responsible for phasic inhibition. We wanted to assess the excitability of hippocampal pyramidal cell (PC) networks following a selective impairment of tonic inhibition. This is difficult to accomplish by pharmacological means. Since the GABAR 
5 subunits mostly mediate the tonic inhibition in CA1 and CA3 PCs, we quantified changes in tonic inhibition and examined network excitability in slices of adult
gabra5-/- mice. In gabra5-/- CA1 and CA3 PCs tonic inhibitory currents were 60% and 53% respectively of those recorded in WT, with no alterations in phasic inhibition. The amount of tonic inhibition recorded in slices was significantly affected by the method of slice storage (interface or submerged chamber). Field recordings in gabra5-/- CA3 pyramidal layer showed increased network excitability. This could be decreased by the GABAR agonist muscimol at a concentration that restored the tonic inhibition of gabra5-/- PCs to WT level without altering phasic inhibition. Through a battery of pharmacological experiments, we have identified 
subunit-containing GABARs as the mediators of the residual tonic inhibition in gabra5-/- PCs. Our study is consistent with an important role of tonic inhibition in the control of hippocampal network excitability, and highlights selective enhancers of tonic inhibition as promising therapeutic approaches for diseases involving network hyperexcitability.
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