Input-Specific Synaptic Location and Function of the α5 GABA Receptor Subunit in the Mouse CA1 Hippocampal Neurons.

Hippocampus-dependent learning processes are coordinated via a large diversity of GABAergic inhibitory mechanisms. The α5 subunit-containing GABA receptor (α5-GABAR) 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-GABAR and, accordingly, its location site-specific function. We examined the cell- and synapse-specific distribution of the α5-GABAR 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-GABAR in spatial learning and anxiety-related behavior was studied using behavioral testing and chemogenetic manipulations. We demonstrate that α5-GABAR is preferentially targeted to the inhibitory synapses made by the vasoactive intestinal peptide (VIP)- and calretinin-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-GABAR. Inhibiting the α5-GABAR in control mice improved spatial learning but also induced anxiety-like behavior. Inhibiting the α5-GABAR 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-GABAR-mediated phasic inhibition via VIP input to interneurons plays a predominant role in the regulation of anxiety while the α5-GABAR tonic inhibition via this subunit may control spatial learning. The α5-GABAR 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-GABAR 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.