- • Hippocampal oscillations are thought to be important for memory encoding and retrieval and depend on inhibition via GABA synapses.
- • GABAA receptor subunits are differentially expressed throughout the hippocampal circuitry. Here we address which subunit controls cholinergically induced fast network oscillations and where it is expressed.
- • By selectively increasing and decreasing the function of α1 and α2 subunits, we find that hippocampal oscillations are controlled by α2 subunits expressed in CA3.
- • Synapses from fast spiking interneurons to pyramidal cells in CA3 that provide the perisomatic inhibition necessary for fast network oscillations contain GABAA receptors with the α2 subunit.
- • Our data suggest that α2-containing GABA receptors in CA3 have an important role in rhythmic hippocampal activity and thereby possibly in cognitive processing.
Abstract GABAA receptors are critically involved in hippocampal oscillations. GABAA receptor α1 and α2 subunits are differentially expressed throughout the hippocampal circuitry and thereby may have distinct contributions to oscillations. It is unknown which GABAA receptor α subunit controls hippocampal oscillations and where these receptors are expressed. To address these questions we used transgenic mice expressing GABAA receptor α1 and/or α2 subunits with point mutations (H101R) that render these receptors insensitive to allosteric modulation at the benzodiazepine binding site, and tested how increased or decreased function of α subunits affects hippocampal oscillations. Positive allosteric modulation by zolpidem prolonged decay kinetics of hippocampal GABAergic synaptic transmission and reduced the frequency of cholinergically induced oscillations. Allosteric modulation of GABAergic receptors in CA3 altered oscillation frequency in CA1, while modulation of GABA receptors in CA1 did not affect oscillations. In mice having a point mutation (H101R) at the GABAA receptor α2 subunit, zolpidem effects on cholinergically induced oscillations were strongly reduced compared to wild-type animals, while zolpidem modulation was still present in mice with the H101R mutation at the α1 subunit. Furthermore, genetic knockout of α2 subunits strongly reduced oscillations, whereas knockout of α1 subunits had no effect. Allosteric modulation of GABAergic receptors was strongly reduced in unitary connections between fast spiking interneurons and pyramidal neurons in CA3 of α2H101R mice, but not of α1H101R mice, suggesting that fast spiking interneuron to pyramidal neuron synapses in CA3 contain α2 subunits. These findings suggest that α2-containing GABAA receptors expressed in the CA3 region provide the inhibition that controls hippocampal rhythm during cholinergically induced oscillations.