Deletion of Bmal1 in the Prelimbic Cortex Glutamatergic Neurons Triggers Schizophrenia-Like Behaviors in Mice.

BACKGROUND: While circadian disturbances are commonly comorbid with schizophrenia (SCZ), whether deficits in clock genes can induce SCZ-like behaviors in mice remains poorly understood. Brain and muscle Arnt-like protein 1 (Bmal1, also known as Mop3 or Arntl), a core circadian clock gene, is implicated in the regulation of circadian rhythms, and its single nucleotide polymorphism rs1982350 has been linked to the pathogenesis of SCZ. STUDY DESIGN: In the present study, we employed global or conditional Bmal1 knockout mouse models to explore the effects of Bmal1 deficiency on SCZ-like phenotypes. STUDY RESULTS: We found that global Bmal1 deletion resulted in hyperactivity, social impairment, anhedonia-like behavior, impaired pre-pulse inhibition, and cognitive deficits in mice, all of which recapitulate the core behavioral abnormalities characteristic of SCZ. Furthermore, enhanced excitability of glutamatergic neurons was identified in the prelimbic cortex (PrL) of Bmal1 knockout mice. Importantly, conditional Bmal1 deletion that specifically triggers localized circadian disruption in PrL glutamatergic neurons replicated the negative symptoms and cognitive deficits associated with SCZ, in the absence of hyperactivity and anhedonia-like behaviors. Mechanistically, Bmal1 in PrL glutamatergic neurons mediates SCZ-related negative symptoms and cognitive deficits via the glutamatergic projection from the PrL to the striatum. CONCLUSIONS: Together, these results reveal a previously unidentified role for Bmal1 deficiency in the PrL in driving SCZ-relevant negative symptoms and cognitive dysfunction. Our findings provide experimental evidence supporting a putative role for dysregulated circadian clock gene expression in the pathogenesis of SCZ.