Reduced Brd1 expression leads to reversible depression-like behaviors and gene-expression changes in female mice

Rajkumar, Anto P.; Qvist, Per; Donskov, Julie G.; Lazarus, Ross; Pallesen, Jonatan; Nava, Nicoletta; Winther, Gudrun; Liebenberg, Nico; La Cour, Sanne H.; Paternoster, Veerle; Fryland, Tue; Palmfeldt, Johan; Fejgin, Kim; Mørk, Arne; Nyegaard, Mette; Pakkenberg, Bente; Didriksen, Michael; Nyengaard, Jens R.; Wegener, Gregers; Mors, Ole; Christensen, Jane H.; Børglum, Anders D.

Abstract

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood. In this study, we assess affective behaviors and associated neurobiology in Brd1+/− mice along with their responses to Fluoxetine and Imipramine. This involves behavioral, neurostructural, and neurochemical characterizations along with regional cerebral gene expression profiling combined with integrative functional genomic analyses. We report behavioral changes in female Brd1+/− mice with translational value to depressive symptomatology that can be alleviated by the administration of antidepressant medications. Behavioral changes are accompanied by altered brain morphometry and imbalances in monoaminergic systems. In accordance, gene expression changes across brain tissues reveal altered neurotransmitter signaling and cluster in functional pathways associated with depression including ‘Adrenergic-, GPCR-, cAMP-, and CREB/CREM-signaling’. Integrative gene expression analysis specifically links changes in amygdaloid intracellular signaling activity to the behavioral treatment response in Brd1+/− mice. Collectively, our study highlights the importance of BRD1 as a modulator of affective pathology and adds to our understanding of the molecular mechanisms underlying affective disorders and their treatment response.

• Journal Article Type: Article
• Acceptance Date: Jun 30, 2020
• Online Publication Date: Jul 17, 2020
• Publication Date: 2020
• Deposit Date: Jul 2, 2020
• Publicly Available Date: Jul 17, 2020
• Journal: Translational Psychiatry
• Electronic ISSN: 2158-3188
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 1
• Article Number: 239
• DOI: https://doi.org/10.1038/s41398-020-00914-2
• Keywords: Biological Psychiatry; Cellular and Molecular Neuroscience; Psychiatry and Mental health
• Public URL: https://nottingham-repository.worktribe.com/output/4742695
• Publisher URL: https://www.nature.com/articles/s41398-020-00914-2
• Additional Information: Received: 3 February 2020; Revised: 20 June 2020; Accepted: 30 June 2020; First Online: 17 July 2020; : Besides being employed by H. Lundbeck A/S, K.F., A.M., and M.D. declare no biomedical financial interests or potential conflicts of interest. A.P.R., P.Q., J.G.D., R.L., Jon.P., N.N., Gu.W., N.L., S.H.l.C., V.P., T.F., Joh.P., M.N., B.P., J.R.N., Gr.W., O.M., J.H.C., and A.D.B. report no biomedical financial interests or potential conflicts of interest.