Altered GABA_A,slowInhibition and Network Oscillations in Mice Lacking the GABA_AReceptor β₃Subunit

Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABAA,fastand GABAA,slow. In hippocampal area CA1, GABAA,fastis generally believed to underlie gamma oscillations, whereas the contribution of GABAA,slowto hippocampal rhythms has been speculative. Hypothesizing that GABAAreceptors containing the β3subunit contribute to GABAA,slowinhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABAAreceptor β3subunit-deficient (β3−/−) mice, spontaneous GABAA,slowinhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABAA,slowcurrents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing β3subunits contribute substantially to GABAA,slowcurrents in pyramidal neurons. By contrast, slow inhibitory control of GABAA,fast-producing interneurons was unaffected in β3−/−mice. In vivo hippocampal network activity was markedly different in the two genotypes. In β3−/−mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency (“nesting”) was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of β3subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABAA,fast-producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.