Characterization of the expression and function of schizophrenia risk gene Dtnbp1 in the suprachiasmatic nucleus

Abstract

Schizophrenia (SZ) is a debilitating neurodevelopmental disorder with environmental and genetic origins. Circadian rhythm disruption is observed in a large proportion of patients with SZ. We previously found that Sandy (Sdy) mice, which carry a mutation in the SZ-associated gene dystrobrevin binding protein 1 (Dtnbp1, also called Dysbindin-1), show altered rhythms of locomotor activity. To address the possible mechanisms underlying the circadian phenotype of these mice, we set out to address the expression and function of Dtnbp1 in the suprachiasmatic nucleus (SCN), the location of the central circadian clock in mammals. Immunohistochemistry revealed that DTNBP1 protein was expressed throughout the SCN, with stronger expression in the dorsal part. DTNBP1 immunoreactive signal colocalized with neurons expressing either arginine vasopressin peptide (AVP) or vasoactive intestinal peptide (VIP). Fluorescent in situ hybridization showed a time-dependent variation of expression of Dtnbp1 transcript, and confirmed its location in cell bodies of AVP- and VIP-expressing cells. Since DTNBP1 is known to be implicated in synaptic transmission, we studied the effect of Dtnbp1 gene mutation on SCN neuropeptide expression and neuroanatomy in Sdy mice. There was no significant effect of the Dtnbp1 mutation on AVP and VIP expression in the SCN. We then used transmission electron microscopy to study synaptic morphology and secretory vesicles. There was no effect of the Dtnbp1 mutation on these neuroanatomical features. Our data show that Dtnbp1 is expressed with a daily rhythm across the SCN, but that a loss-of-function mutation did not impair AVP or VIP neuropeptide expression nor general synaptic architecture.