Mismatch novelty exploration training shifts VPAC1receptor mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats

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. Inhibition of VIP interneurons by prefrontal cortex GABAergic projections promotes rodent exploration. Since VIP, acting on VPAC 1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition we now investigated the impact of NT on VPAC 1 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 VPAC 1 Rs with PG 97-269 (100nM) 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 VPAC 1 R levels but neither VIP nor VPAC 1 R 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 VPAC 1 Rs is associated to 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. Significance statement This work sheds light into the contribution of hippocampal neuropeptide VIP and VIP containing GABAergic neurons on the reformulation of hippocampal circuit communication leading to altered synaptic plasticity responses upon training in repeated exposure to object mismatch novelty as compared with routine training paradigms with and without objects. Although still far from the clinic, the results suggest that VIP receptor ligands may be useful to co-adjuvate cognitive stimuli therapies based on these aspects of novelty, aiming at the cognitive rescue of aged individuals or epilepsy patients, that show impaired capacity in novelty induced adaptations of cognitive function. Graphical abstract