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.
Microglia can interact with glutamatergic neurons and, through control of synaptic elements, regulate their physiological function. Much less is known about the partnership between microglia and GABAergic inhibitory interneurons. Here, we compared the interactions between microglia and parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the CA1 hippocampal area of APP/PS1 transgenic mice that mimic certain aspects of the Alzheimer's disease (AD). We first uncovered a high level of interactions between microglia and two types of interneurons, with 98% of SOM+ and 90% of PV+ cells receiving different types of putative microglial contacts. The latter included the microglia soma to the interneuron soma (SomaMG‐to‐SomaIN), the microglia process to the interneuron soma (ProcessMG‐to‐SomaIN) and the microglia process to the interneuron dendrite (ProcessMG‐to‐DendIN) interactions. Moreover, we found significantly larger areas of interaction for the SomaMG‐to‐SomaIN and the ProcessMG‐to‐DendIN type of contacts between microglia and SOM+ cells. In contrast, PV+ cells exhibited larger areas for the ProcessMG‐to‐SomaIN interactions. Second, in APP/PS1 mice, although the overall microglia interactions with interneurons remained preserved, the fraction of interneurons receiving putative microglia contacts on their dendrites was reduced, and larger areas of interactions were observed for somatic contacts, suggesting a stronger modulation of the interneuron output by microglia in AD. In summary, these results reveal microglia as important partners of hippocampal PV+ and SOM+ GABAergic cells, with interneuron type‐specific pattern of interactions. Thus, microglia may play an essential role in the operation of interneurons under normal conditions and their dysfunction in disease.
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