In cortical networks, different types of inhibitory interneurons control the activity of glutamatergic principal cells and GABAergic

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

It has been recognized for some time that different subtypes of cortical inhibitory interneurons innervate specific dendritic domains of principal cells and release GABA at particular times during behaviorally relevant network oscillations. However, the lack of basic information on how the activity of interneurons can be controlled by GABA released in particular behavioral states has hindered our understanding of the rules that govern the spatio-temporal organization and function of dendritic inhibition. Similar to principal cells, any given interneuron may receive several functionally distinct inhibitory inputs that target its specific subcellular domains. We recently found that local circuitry of the so-called interneuron-specific (IS) interneurons is responsible for dendritic inhibition of different subtypes of hippocampal interneurons with a great impact on cell output. Here, we will review the properties and the specificity of connections of IS interneurons in the CA1 hippocampus and neocortex, and discuss their possible role in the activity-dependent regulation of dendritic inhibition received by pyramidal neurons.