Input-specific synaptic location and function of the alpha5 GABAA receptor subunit in the mouse CA1 hippocampal neurons.

Hippocampus-dependent learning processes are coordinated via a large diversity of GABAergic inhibitory mechanisms. The alpha5 subunit-containing GABAA receptor (α5-GABAA R) is abundantly expressed in the hippocampus populating primarily the extrasynaptic domain of CA1 pyramidal cells, where it mediates tonic inhibitory conductance and may cause functional deficits in synaptic plasticity and hippocampus-dependent memory. However, little is known about synaptic expression of the α5-GABAA R and, accordingly, its location site-specific function. We examined the cell- and synapse-specific distribution of the α5-GABAA R in the CA1 stratum oriens/alveus (O/A) using a combination of immunohistochemistry, whole-cell patch-clamp recordings and optogenetic stimulation in hippocampal slices obtained from mice of either sex. In addition, the input-specific role of the α5-GABAA R in spatial learning and anxiety-related behavior was studied using behavioral testing and chemogenetic manipulations. We demonstrate that α5-GABAA R is preferentially targeted to the inhibitory synapses made by the vasoactive intestinal peptide (VIP)- and calretinin (CR)-positive terminals onto dendrites of somatostatin-expressing interneurons. In contrast, synapses made by the parvalbumin-positive inhibitory inputs to O/A interneurons showed no or little α5-GABAA R. Inhibiting the α5-GABAA R in control mice in vivo improved spatial learning but also induced anxiety-like behavior. Inhibiting the α5-GABAA R in mice with inactivated CA1 VIP input could still improve spatial learning and was not associated with anxiety. Together, these data indicate that the α5-GABAA R-mediated phasic inhibition via VIP input to interneurons plays a predominant role in the regulation of anxiety while the α5-GABAA R tonic inhibition via this subunit may control spatial learning. SIGNIFICANCE STATEMENT The α5-GABAA R subunit exhibits high expression in the hippocampus, and regulates the induction of synaptic plasticity and the hippocampus-dependent mnemonic processes. In CA1 principal cells, this subunit occupies mostly extrasynaptic sites and mediates tonic inhibition. Here, we provide evidence that, in CA1 somatostatin-expressing interneurons, the α5-GABAA R subunit is targeted to synapses formed by the VIP- and calretinin-expressing inputs, and plays a specific role in the regulation of anxiety-like behavior.