Altered GABAA,slow inhibition and network oscillations in mice lacking the GABAA receptor beta3 subunit

Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABA(A,fast) and GABA(A,slow). In hippocampal area CA1, GABA(A,fast) is generally believed to underlie gamma oscillations, whereas the contribution of GABA(A,slow) to hippocampal rhythms has been speculative. Hypothesizing that GABA(A) receptors containing the beta(3) subunit contribute to GABA(A,slow) inhibition 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 GABA(A) receptor beta(3) subunit-deficient (beta(3)(-/-)) mice, spontaneous GABA(A,slow) inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABA(A,slow) currents 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 beta(3) subunits contribute substantially to GABA(A,slow) currents in pyramidal neurons. By contrast, slow inhibitory control of GABA(A,fast)-producing interneurons was unaffected in beta(3)(-/-) mice. In vivo hippocampal network activity was markedly different in the two genotypes. In beta(3)(-/-) 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 beta(3) subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABA(A,fast) -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.