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Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory


The hippocampus contains a diverse array of inhibitory interneurons that gate information flow through local cortico-hippocampal circuits to regulate memory storage. Although most studies of interneurons have focused on their role in fast synaptic inhibition mediated by GABA release, different classes of interneurons express unique sets of neuropeptides, many of which have been shown to exert powerful effects on neuronal function and memory when applied pharmacologically. However, relatively little is known about whether and how release of endogenous neuropeptides from inhibitory cells contributes to their behavioral role in regulating memory formation. Here we report that vasoactive intestinal peptide (VIP)-expressing interneurons participate in social memory storage by enhancing information transfer from hippocampal CA3 pyramidal neurons to CA2 pyramidal neurons. Notably, this action depends on release of the neuropeptide enkephalin from VIP neurons, causing long-term depression of feedforward inhibition onto CA2 pyramidal cells. Moreover, VIP neuron activity in the CA2 region is increased selectively during exploration of a novel conspecific. Our findings, thus, enhance our appreciation of how GABAergic neurons can regulate synaptic plasticity and mnemonic behavior by demonstrating that such actions can be mediated by release of a specific neuropeptide, rather than through classic fast inhibitory transmission.

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Fig. 1: VIP and enkephalin expression overlaps in the hippocampal CA2 region.
Fig. 2: VIP neurons are necessary and sufficient to induce CA2 ITDP through DOR activation.
Fig. 3: Enkephalin is necessary for ITDP induction.
Fig. 4: VIP neurons receive excitatory inputs from both CA3 and EC layer II stellate cells.
Fig. 5: Silencing VIP neurons impairs social memory formation.
Fig. 6: Enkephalin expression in CA2 region is necessary for social memory.
Fig. 7: Activity of VIP neurons in CA2 increases specifically during interaction with a novel mouse.


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This work was supported by: a 2019 NARSAD young investigator grant to FL from the Brain and Behavior research foundation, funded by the Osterhaus Family; a F32 MH122147-01A1 to CdS; Howard Hughes Medical Institute support to ERK and R01-MH104602 and R01-MH106629 to SAS.

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Conceptualization: FL and SAS; investigation, FL, TB, CAdS, AA, LB, OML, and EB; in vitro intra-cellular recordings: FL and TB; behavioral assays and viral injections: FL and OML; immunohistochemistry and in situ hybridization: FL, CdS, and AA; shRNA design CAdS and AA, Calcium imaging: LMB writing—original draft: FL; writing—review and editing: FL, AA, ERK, and SAS; visualization: FL; supervision: FL; funding acquisition: FL, CAdS, ERK, and SAS.

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Correspondence to Felix Leroy or Steven A. Siegelbaum.

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Leroy, F., de Solis, C.A., Boyle, L.M. et al. Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory. Mol Psychiatry (2021).

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