Mismatch novelty exploration training shifts VPAC₁ receptor‐mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats

Abstract

Novelty influences hippocampal‐dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal‐dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD‐95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP‐expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co‐adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.