DISI​​​​NHIBITORY CONTROL BY SUBICULAR VIP INTERNEURONS SHAPES HIPPOCAMPAL OUTPUT AND BEHAVIOUR

The subiculum, the primary output node of the hippocampal formation, is implicated in several psychiatric disorders. Dysfunction of GABAergic interneurons has been proposed to drive hippocampal hyperactivity associated with these conditions. We hypothesised that impaired inhibitory control within the subicular interneuron network contributes to this hyperactivity. Vasoactive intestinal polypeptide (VIP)–expressing interneurons, which are abundant in the subiculum, inhibit other interneurons across brain regions. We therefore propose that subicular VIP interneurons regulate local network excitability and hippocampal output by inhibiting other interneurons, and that their dysfunction may produce behavioural deficits. To test this, we used chemogenetic activation of VIP interneurons in the ventral subiculum of behaving mice. Circuit mechanisms were examined using optogenetic and pharmacological manipulations combined with slice electrophysiology. Chemogenetic excitation of VIP interneurons impaired sensory-motor gating and spatial working memory. Optogenetic-assisted circuit mapping revealed that subicular VIP interneurons preferentially target non-VIP interneurons, forming a disinhibitory motif. Consistent with this, activation of VIP interneurons increased pyramidal neuron excitability. Pharmacological application or release of VIP similarly enhanced pyramidal excitability by modulating GABA release, increasing it at VPAC2 receptor-expressing synapses but suppressing it at VPAC1 receptor-expressing synapses. GABA and VIP co-released from subicular VIP interneurons synergistically regulate local network excitability. These findings identify VIP interneurons as critical modulators of hippocampal output and behaviour, highlighting them as potential therapeutic targets for psychiatric disorders characterised by hippocampal hyperactivity.