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

TitleInput-Specific Synaptic Location and Function of the α5 GABA Receptor Subunit in the Mouse CA1 Hippocampal Neurons.
Publication TypeJournal Article
Year of Publication2019
AuthorsMagnin, E, Francavilla, R, Amalyan, S, Gervais, E, David, LSuzanne, Luo, X, Topolnik, L
JournalJ Neurosci
Volume39
Issue5
Pagination788-801
Date Published2019 Jan 30
ISSN1529-2401
Abstract

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.

DOI10.1523/JNEUROSCI.0567-18.2018
Alternate JournalJ. Neurosci.
PubMed ID30523065