Excitatory actions of vasoactive intestinal peptide on mouse thalamocortical neurons are mediated by VPAC₂ receptors

Thalamic nuclei can generate intrathalamic rhythms similar to those observed at various arousal levels and pathophysiological conditions such as absence epilepsy. These rhythmic activities can be altered by a variety of neuromodulators that arise from brain stem regions as well as those that are intrinsic to the thalamic circuitry. Vasoactive intestinal peptide (VIP) is a neuropeptide localized within the thalamus and strongly attenuates intrathalamic rhythms via an unidentified receptor subtype. We have used transgenic mice lacking a specific VIP receptor, VPAC₂, to identify its role in VIP-mediated actions in the thalamus. VIP strongly attenuated both the slow, 2-4 Hz and spindle-like 5-8 Hz rhythmic activities in slices from wild-type mice (VPAC₂^+/+) but not in slices from VPAC₂ receptor knock-out mice (VPAC₂^-/-), which suggests a major role of VPAC₂ receptors in the antioscillatory actions of VIP. Intracellular recordings revealed that VIP depolarized all relay neurons tested from VPAC₂^+/+ mice. In VPAC₂^-/- mice, however, VIP produced no membrane depolarization in 80% of neurons tested. In relay neurons from VPAC₂+/+ mice, VIP enhanced the hyperpolarization-activated mixed cation current, I_h, via cyclic AMP activity, but VIP did not alter I_H in VPAC₂-/- mice. In VPAC₂-/- mice, pituitary adenylate cyclase activating-polypeptide (PACAP) depolarized the majority of relay neurons via I_H enhancement presumably via PAC₁ receptor activation. Our findings suggest that VIP-mediated actions are predominantly mediated by VPAC₂ receptors, but PAC₁ receptors may play a minor role. The excitatory actions of VIP and PACAP suggest these peptides may not only regulate intrathalamic rhythmic activities, but also may influence information transfer through thalamocortical circuits.