Excitatory actions of peptide histidine isoleucine on thalamic relay neurons

Peptide histidine isoleucine (PHI) and vasoactive intestinal peptide (VIP) are neuropeptides synthesized from a common precursor, prepro-VIP, and share structural similarity and biological functions in many systems. Within the central nervous system and peripheral tissues, PHI and VIP have overlapping distribution. PHI-mediated functions are generally via activation of VIP receptors; however, the potency and affinity of PHI for VIP receptors are significantly lower than VIP. In addition, several studies suggest distinct PHI receptors that are independent of VIP receptors. PHI receptors have been cloned and characterized in fish, but their existence in mammals is still unknown. This study focuses on the functional role of PHI in the thalamus because of the localization of both PHI and VIP receptors in this brain region. Using extracellular multiple-unit recording techniques, we found that PHI strongly attenuated the slow intrathalamic rhythmic activity. Using intracellular recording techniques, we found that PHI selectively depolarized thalamic relay neurons via an enhancement of the hyperpolarization-activated mixed cation current, I_h. Further, the actions of PHI were occluded by VIP and dopamine, indicating these modulators converge onto a common mechanism. In contrast to previous work, we found that PHI was more potent than VIP in producing excitatory actions on thalamic neurons. We next used the transgenic mice lacking a specific VIP receptor, VPAC₂, to identify its possible role in PHI-mediated actions in the thalamus. PHI depolarized all relay neurons tested from wild-type mice (VPAC₂^+/+); however, in knockout mice (VPAC₂^-/-), PHI produced no change in membrane potential in all neurons tested. Our findings indicate that excitatory actions of PHI are mediated by VPAC₂ receptors, not by its own PHI receptors and the excitatory actions of PHI clearly attenuate intrathalamic rhythmic activities, and likely influence information transfer through thalamocortical circuits.