GABAA receptors containing α2 subunits, and not α1 subunits, on CA3 pyramidal neurons control hippocampal fast network oscillations

Inhibitory GABAergic synaptic currents are the predominant current source underlying hippocampal oscillations in vitro and their kinetics controls the frequency of these oscillations. Since GABAergic synapse kinetics is determined by the α subunit type expressed in the synaptic GABA A receptors, expression of these subunits will most likely affect properties of hippocampal oscillations. It is unknown which GABA A receptor α subunit controls hippocampal oscillations. To address this question we used trans-genic mice expressing GABA A receptor α1 and/or α2 subunits with point mutations that render these receptors insensitive to allosteric modulation at the benzodiazepine binding site, and tested how increased or decreased function of α subunits affects hip-pocampal oscillations. In hippocampus of wild-type mice, positive allosteric modulation prolonged decay kinetics of GABAergic synaptic transmission and reduced the frequency of cholinergically-induced oscillations. These effects were almost absent in mice expressing α2 subunits that were insensitive to allosteric modulation: IPSC kinet-ics in CA3 pyramidal neurons as well as fast network oscillations showed a largely reduced sensitivity to allosteric modulation. In contrast, in mice expressing insensitive α1 subunits, IPSC kinetics and fast network oscillations were sensitive to allosteric modulation. Genetic knockout of α2 subunits strongly reduced fast network oscillations, whereas knockout of α1 subunits had no effect. Local application of allosteric modu-lators to either CA3 or CA1 region in wild type mice showed that GABA A receptors located in CA3 determine the frequency of oscillations in the entire hippocampal slice. Our findings suggest that GABA A receptors containing α2 receptor subunits expressed by CA3 pyramidal cells control the frequency of cholinergically-induced hippocampal oscillations.