Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment

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Abstract

Graphical abstract

CMS exposure modulated transcription and translation of clock genes primarily in the prefrontal cortex, and chronic treatment with antipsychotic lurasidone is able to normalize some of these alterations. Indeed, respect to the basal condition (Panel A), stress exposure (Panel B) reduced the protein levels of BMAL1, CLOCK and GR in the nuclear compartments producing a decrease in the expression of the Rev-Erbs, Pers and Crys genes. In turn the reduction of Rev-Erbβ and of Hdac mRNA levels may underlie the decreased transcription of Bmal1. Moreover, the effect on Pers and Crys gene was paralleled by a similar alteration of the protein levels. On the other side, chronic treatment with lurasidone (Panel C) was able to restore the normal protein levels BMAL1 and GR with consequent normalization of the expression of the target genes. Moreover, the expression of Bmal1 was, here, similar to those observed in basal condition (Panel A) probably because also Rev-Erbβ and of Hdac mRNA levels were normalized by the pharmacological treatment. Finally, lurasidone was able to correct only the alteration due to the CMS of CRY1.

Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverbβ and Pparα.

Interestingly, chronic treatment with the multi receptor modulator lurasidone (3 mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus.

We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders.

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