Endogenous VIP VPAC1 Receptor Activation Modulates Hippocampal Theta Burst Induced LTP: Transduction Pathways and GABAergic Mechanisms.

Abstract

Simple SummaryRegulation 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 scarcely been investigated. We studied the modulation of CA1 LTP induced by TBS via endogenous VIP release in hippocampal slices from young-adult Wistar rats using selective VPAC1 and VPAC2 receptor antagonists, evaluating its consequence for the phosphorylation of CamKII, GluA1 AMPA receptor subunits and Kv4.2 potassium channels in total hippocampal membranes obtained from TBS stimulated slices. Endogenous VIP, acting on VPAC1 (but not VPAC2) receptors, inhibited CA1 hippocampal LTP induced by TBS in young adult Wistar rats and this effect was dependent on GABAergic transmission and relied on the integrity of NMDA and CaMKII-dependent LTP expression mechanisms but not on PKA and PKC activity. Furthermore, it regulated the autophosphorylation of CaMKII and the expression and Ser438 phosphorylation of Kv4.2 potassium channels responsible for the A-current while inhibiting phosphorylation of Kv4.2 on Thr607. Altogether, this suggests that endogenous VIP controls the expression of hippocampal CA1 LTP by regulating disinhibition through activation of VPAC1 receptors in interneurons. This may impact the autophosphorylation of CaMKII during LTP, as well as the expression and phosphorylation of Kv4.2 K+ channels at hippocampal pyramidal cell dendrites.