Hippocampus-dependent learning processes are coordinated via a large diversity of
GABAergic inhibitory mechanisms. The alpha 5 subunit-containing GABA(A) receptor (alpha
5-GABA(A)R) is abundantly expressed in the hippocampus populating primarily the extra-synaptic
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 alpha 5-GABA(A)R and, accordingly,
its location site-specific function. We examined the cell- and synapse-specific distribution
of the alpha 5-GABA(A)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 alpha 5GABA(A)R in spatial learning and anxiety-related behavior was studied
using behavioral testing and chemogenetic manipulations. We demonstrate that alpha
5-GABA(A)R 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 alpha 5-GABA(A)R. Inhibiting the alpha 5-GABA(A)R
in control mice in vivo improved spatial learning but also induced anxiety-like behavior.
Inhibiting the alpha 5-GABA(A)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 alpha 5-GABA(A)R-mediated phasic inhibition via VIP input to interneurons
plays a predominant role in the regulation of anxiety while the alpha 5-GABA(A)R tonic
inhibition via this subunit may control spatial learning.