Mismatch novelty exploration training impairs VPAC1 receptor mediated modulation of hippocampal synaptic plasticity by endogenous VIP

Novelty influences hippocampal-dependent memory through metaplasticity, i.e., experience-dependent adaptations in synaptic plasticity. In this respect, mismatch novelty is known to activate the hippocampal CA1 area in humans and to enhance rat hippocampal-dependent learning and exploration. Mismatch novelty training (NT) by varying spatial configuration of objects in a known environment, enhances rat hippocampal synaptic plasticity. Prefrontal cortex GABAergic projections targeting hippocampal VIP interneurons promote exploration. Since VIP, acting on VPAC1 receptors, restrains both hippocampal LTP and depotentiation by modulating disinhibition we now investigated the impact of NT on VPAC1 receptor modulation of hippocampal synaptic plasticity. NT enhanced both CA1 hippocampal long-term potentiation (LTP) and depotentiation. Blockade of VIP VPAC1 receptors with PG 97-269 (100nM) enhanced both LTP and depotentiation in naïve animals but was much less effective in enhancing LTP and depotentiation in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). Modulation of depotentiation by endogenous VIP was absent in animals exposed to a fixed configuration of objects (FT) or in HT animals. HT and FT animals, but not NT; showed mildly enhanced synaptic VPAC1 receptor expression. Altogether this suggests that NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons. Also, upregulation of VIP VPAC1 receptors maintains VIP control of LTP in FT and HT rats, the absence of this in NT rats leading to enhanced LTP but not influencing depotentiation. This may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs. Graphical abstract Impairment of endogenous VIP VPAC1 receptor modulation of hippocampal CA1 LTP and depotentiation upon mismatch novelty training. Highlights Mismatch novelty training (NT) enhances hippocampal CA1 LTP and depotentiation. Endogenous VIP VPAC1 receptor modulation of synaptic plasticity is lessened by NT. NT does not influence hippocampal levels of VIP or VPAC1 receptors. NT and VIP likely impact coincident paths to control LTP and depotentiation.