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Disrupted Neuronal Activity Rhythms in the Suprachiasmatic Nuclei of Vasoactive Intestinal Polypeptide-Deficient Mice

¹Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and ²Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California

Submitted 15 November 2006; accepted in final form 5 December 2006

Vasoactive intestinal polypeptide (VIP), acting via the VPAC₂ receptor, is a key signaling pathway in the suprachiasmatic nuclei (SCN), the master clock controlling daily rhythms in mammals. Most mice lacking functional VPAC₂ receptors are unable to sustain behavioral rhythms and lack detectable SCN electrical rhythms in vitro. Adult mice that do not produce VIP (VIP/PHI^–/–) exhibit less severe alterations in wheel-running rhythms, but the effects of this deficiency on the amplitude, phasing, or periodicity of their SCN cellular rhythms are unknown. To investigate this, we used suction electrodes to extracellularly record multiple- and single-unit electrical activity in SCN brain slices from mice with varying degrees of VIP deficiency, ranging from wild-type (VIP/PHI^+/+) to heterozygous (VIP/PHI^+/–) and VIP/PHI^–/– animals. We found decreasing proportions of rhythmic cells in SCN slices from VIP/PHI^+/+ (91%, n = 23) through VIP/PHI^-/+ (71%, n = 28) to VIP/PHI^–/– mice (62%; n = 37) and a parallel trend toward decreasing amplitude in the remaining rhythmic cells. SCN neurons from VIP/PHI^–/– mice exhibited a broad range in the period and phasing of electrical rhythms, concordant with the known alterations in their behavioral rhythms. Further, treatment of VIP/PHI^–/– slices with a VPAC₂ receptor antagonist significantly reduced the proportion of oscillating neurons, suggesting that VPAC₂ receptors still become activated in the SCN of these mice. The results establish that VIP is important for appropriate periodicity and phasing of SCN neuronal rhythms and suggest that residual VPAC₂ receptor signaling promotes rhythmicity in adult VIP/PHI^–/– mice.

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