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.