Role of subicular VIP interneurons in modulating the hippocampal output and behaviour

The subiculum, a hippocampal subfield that functions as the final gate for most hippocampal outputs, is implicated in various psychiatric disorders. Accumulating evidence suggests that dysfunction in multiple GABAergic interneuron types is a key factor in the pathologic presentation of hippocampal hyperactivity associated with these disorders. We posit that dysfunction in the inhibitory control of interneurons in the subiculum may be a key network mechanism for the emergence of hippocampal hyperactivity. In several brain regions, a special class of interneurons known as vasoactive intestinal polypeptide-expressing (VIP) interneurons assume this role of inhibitory control of other interneurons. Given the robust expression of VIP interneurons in the subiculum, we hypothesize that these interneurons strongly modulate the local network and hippocampal output via inhibition of other interneurons, and their dysfunction can lead to behavioural deficits. To test this hypothesis, we used a chemogenetic approach to over-activate VIP interneurons in the ventral subiculum and probe their role in behaviour. Our results showed that chemogenetic excitation of VIP interneurons in the ventral subiculum impaired prepulse inhibition of startle response and spatial working memory. To better understand how subicular VIP interneurons modulate local circuits, we used optogenetic manipulation and slice electrophysiology. Our ChR2-assisted circuit mapping results indicated that subicular VIP interneurons have low connectivity with pyramidal cells, and higher connectivity with non-VIP interneurons, suggesting a disinhibitory role. In line with this finding, activation of VIP interneurons also increased excitability in subicular pyramidal cells, but not non-VIP interneurons.