The role of subicular VIP-expressing interneurons on seizure dynamics in the intrahippocampal kainic acid model of temporal lobe epilepsy.

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control.

Single stimulation of Y2 receptors in BNSTav facilitates extinction and dampens reinstatement of fear.

RATIONALE: Return of fear by re-exposure to an aversive event is a major obstacle in the treatment of fear-related disorders. Recently, we demonstrated that local pharmacological stimulation of neuropeptide Y type 2 receptors (Y2R) in anteroventral bed nucleus of stria terminalis (BNSTav) facilitates fear extinction and attenuates retrieval of remote fear with or without concomitant extinction training. Whether Y2R activation could also protect against re-exposure to traumatic events is still unknown. OBJECTIVE: Therefore, we investigated reinstatement of remote fear following early Y2R manipulation in BNSTav in relation to concomitant extinction training in mice. METHODS: We combined local pharmacological manipulation of Y2Rs in BNSTav with or without extinction training and tested for reinstatement of remote fear 15 days later. Furthermore, we employed immediate early gene mapping to monitor related local brain activation. RESULTS: Y2R stimulation by local injection of NPY3-36 into BNSTav facilitated extinction, reduced fear reinstatement at remote stages, and mimicked the influence of extinction in groups without prior extinction training. In contrast, Y2R antagonism (JNJ-5207787) delayed extinction and increased reinstatement. Y2R treatment immediately before remote fear tests had no effect. Concomitantly, Y2R activation at early time points reduced the number of c-Fos positive neurons in BNSTav during testing of reinstated remote fear. CONCLUSION: Local Y2R stimulation in BNSTav promotes fear extinction and stabilizes suppression of reinstated fear through a long-term influence, even without extinction training. Thus, Y2Rs in BNST are crucial pharmacological targets for extinction-based remote fear suppression.