Gastrin-releasing peptide promotes suprachiasmatic nuclei cellular rhythmicity in the absence of vasoactive intestinal polypeptide-VPAC2 receptor signaling

Vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP) acting via the VPAC(2) receptor and BB2 receptors, respectively, are key signaling pathways in the suprachiasmatic nuclei (SCN) circadian clock. Transgenic mice lacking the VPAC(2) receptor (Vipr2(-/-)) display a continuum of disrupted behavioral rhythms with only a minority capable of sustaining predictable cycles of rest and activity. However, electrical or molecular oscillations have not yet been detected in SCN cells from adult Vipr2(-/-) mice. Using a novel electrophysiological recording technique, we found that in brain slices from wild-type and behaviorally rhythmic Vipr2(-/-) mice, the majority of SCN neurons we detected displayed circadian firing patterns with estimated periods similar to the animals' behavior. In contrast, in slices from behaviorally arrhythmic Vipr2(-/-) mice, only a small minority of the observed SCN cells oscillated. Remarkably, exogenous GRP promoted SCN cellular rhythms in Vipr2(-/-) mouse slices, whereas blockade of BB2 receptors suppressed neuronal oscillations. In wild- type mice, perturbation of GRP- BB2 signaling had few effects on SCN cellular rhythms, except when VPAC2 receptors were blocked pharmacologically. These findings establish that residual electrical oscillations persist in the SCN of Vipr2(-/-) mice and reveal a potential new role for GRP-BB2 signaling within the circadian clock.