Selective deficits in the circadian light response in mice lacking PACAP

Abstract

Previous studies indicate that light information reaches the suprachiasmatic nucleus through a subpopulation of retinal ganglion cells that contain both glutamate and pituitary adenylyl cyclase-activating peptide (PACAP). Although the role of glutamate in this pathway has been well studied, the involvement of PACAP and its receptors is only beginning to be understood. To investigate the functions of PACAP in vivo, we developed a mouse model in which the gene coding for PACAP was disrupted by targeted homologous recombination. RIA was used to confirm a lack of detectable PACAP protein in these mice. PACAP-deficient mice exhibited significant impairment in the magnitude of the response to brief light exposures with both light-induced phase delays and advances of the circadian system impacted. This mutation equally impacted phase shifts induced by bright and dim light exposure. Despite these effects on phase shifting, the loss of PACAP had only limited effects on the generation of circadian oscillations, as measured by rhythms in wheel-running activity. Unlike melanopsin-deficient mice, the mice lacking PACAP exhibited no loss of function in the direct light-induced inhibition of locomotor activity, i.e., masking. Finally, the PACAP-deficient mice exhibited normal phase shifts in response to exposure to discrete dark treatments. The results reported here show that the loss of PACAP produced selective deficits in the light response of the circadian system.

Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

“…Using the type II procedure, we found that the response to light stimulation in PAC1 KO mice differed from our previously obtained results using the type I regime (11). Most striking was the attenuated phase delay found in the type II at early night (increased in type I), a result, however, which accords with that found in two different strains of mice lacking PACAP (4,17). Although the response in WT mice was independent of the regime used, the PAC1 KO mice displayed different light responses at both early and late subjective night.…”

“…In the first study by Kawaguchi et al (17), mice lacking PACAP showed a slightly diminished phase delay but a significantly attenuated phase advance to a single light pulse at early and late night, respectively. In a later study by Colwell et al (4), PACAP-deficient mice exhibited significant impairment in the magnitude of both light-induced phase delay and phase advance (4). We found that the PAC1 receptor-deficient mice displayed a larger phase delay at early night and decreased phase advance at late night (11).…”

“…We have previously shown that the neuropeptide pituitary adenylate cyclase activating peptide (PACAP) is costored with glutamate in the RHT (13) and that the two neurotransmitters are mediators of photic adjustment of the circadian system in a rather complex interplay (9). After the demonstration of PACAP in the RHT, (12) a number of studies have delineated the role of PACAP in light entrainment, which primarily seems to be exerted via the PACAPspecific PACAP receptor type 1 (PAC1) receptor (3,4,11,14,17,23). In vitro, PACAP has been shown to modulate glutamatergic signaling in a time-and concentration-dependent manner targeting the core clock genes Per1 and Per2 via cyclic AMP/PKA and the inositotriphospate/phospholipase C signaling pathway (reviewed in Ref.…”

“…10). In studies on mice lacking either PACAP or the PAC1 receptor, using different regimes of light duration and intensity, they were found to have altered response to photic stimulation at night (4,11,17). In the first study by Kawaguchi et al (17), mice lacking PACAP showed a slightly diminished phase delay but a significantly attenuated phase advance to a single light pulse at early and late night, respectively.…”

“…Mice lacking either PACAP or the PAC1 receptor are able to entrain to the light-dark (LD) cycle (4,11,17), and mice lacking PACAP respond as wild-type (WT) mice to reentrainment of large (8-h) phase shifts of the external LD cycle. Also, masking behavior has been reported to be undisturbed in PACAP knockout (KO) animals (4).…”