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Regulation of synaptic plasticity through control of disinhibition is an important process in the prevention of excessive plasticity in both physiological and pathological conditions. Interneuron-selective interneurons, such as the ones expressing VIP in the hippocampus, may play a crucial role in this process. In this paper we showed that endogenous activation of VPAC₁—not VPAC₂ receptors—exerts an inhibitory control of long-term potentiation (LTP) induced by theta-burst stimulation (TBS) in the hippocampus, through a mechanism dependent on GABAergic transmission. This suggests that VPAC₁-mediated modulation of synaptic transmission at GABAergic synapses to interneurons will ultimately influence NMDA-dependent LTP expression by modulating inhibitory control of pyramidal cell dendrites and postsynaptic depolarization during LTP induction. Accordingly, the transduction pathways mostly involved in this effect were the ones involved in TBS-induced LTP expression like NMDA receptor activation and CaMKII activity. In addition, the actions of endogenous VIP through VPAC₁ receptors may indirectly influence the control of dendritic excitability by Kv4.2 channels.

Vasoactive intestinal peptide (VIP), acting on both VPAC₁ and VPAC₂ receptors, is a key modulator of hippocampal synaptic transmission, pyramidal cell excitability and long-term depression (LTD), exerting its effects partly through modulation GABAergic disinhibitory circuits. Yet, the role of endogenous VIP and its receptors in modulation of hippocampal LTP and the involvement of disinhibition in this modulation have …