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Tonic activation of VPAC1 receptors by VIP modulates theta-burst induced LTP in the hippocampus: transduction pathways and GABAergic mechanisms.
  • +1
  • Nadia Rodrigues,
  • Ana Caulino-Rocha,
  • Joaquim Ribeiro,
  • dcreis
Nadia Rodrigues
Universidade de Lisboa Instituto de Medicina Molecular João Lobo Antunes
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Ana Caulino-Rocha
University of Lisbon Faculty of Sciences
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Joaquim Ribeiro
University of Lisbon Medical Faculty
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Abstract

Background and purpose Vasoactive intestinal peptide (VIP), acting on both VPAC1 and VPAC2 receptors, is a key modulator of hippocampal synaptic transmission, pyramidal cell excitability and synaptic plasticity phenomena, like long-term depression (LTD), partly through modulation GABAergic disinhibitory circuits. VIP effects on LTP and the involvement of disinhibition were scarcely investigated. Experimental approach The influence of endogenous VIP on CA1 LTP induced by TBS was evaluated in the CA1 area of hippocampal slices using field-excitatory electrophysiological recordings from young-adult Wistar rats using selective VPAC1 and VPAC2 antagonists. Phosphorylation of GluA1 AMPA receptor subunits and Kv4.2 potassium channels was evaluated in hippocampal membranes obtained from such slices by Western blot. Key results Here we show that VIP, acting on VPAC1 (but not VPAC2) receptors, is an endogenous inhibitor of hippocampal LTP induced by theta-burst stimulation (TBS) in the CA1 area of the hippocampus of young adult Wistar rats. This effect is dependent on GABAergic transmission and relies on the integrity of NMDA and CaMKII-dependent LTP expression mechanisms but not on PKA and PKC activity. Furthermore, it regulates the expression and Ser438phosphorylation of Kv4.2 potassium channels responsible for the A-current while inhibiting phosphorylation of Kv4.2 on Thr607. Conclusions and implications 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 expression and phosphorylation of Kv4.2 K+ channels at hippocampal pyramidal cell dendrites.

Peer review status:UNDER REVIEW

06 Apr 2021Submitted to British Journal of Pharmacology
07 Apr 2021Assigned to Editor
07 Apr 2021Submission Checks Completed
08 Apr 2021Reviewer(s) Assigned