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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 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 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 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 to maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co …