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

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  • Anto P Rajkumar, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Centre for Integrative Sequencing (iSEQ), Center for Genomics and Personalized Medicine, Division of Psychiatry and Applied Psychology, School of Medicine & Centre for ADHD and Neurodevelopmental Disorders Across the Lifespan & NIHR MindTech Health Care Technology Cooperative, Institute of Mental Health, University of Nottingham, Nottingham, UK., Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK; NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK., UK acrodysostosis patients' group, London, UK., Department of Old Age Psychiatry, Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, London, King's College London School of Medicine, London., Queen Marys Univ London, Queen Mary University London, University of London, Barts & London Sch Med & Dent
  • ,
  • Per Qvist
  • Julie G Donskov, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Centre for Integrative Sequencing (iSEQ), Center for Genomics and Personalized Medicine
  • ,
  • Ross Lazarus, Baker IDI Heart and Diabetes Institute
  • ,
  • Jonatan Pallesen
  • Nicoletta Nava, The Headache Clinic, Aarhus University Hospital, Aarhus, Denmark Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
  • ,
  • Gudrun Winther
  • Nico Liebenberg, The Headache Clinic, Aarhus University Hospital, Aarhus, Denmark Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
  • ,
  • Sanne H la Cour, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Centre for Integrative Sequencing (iSEQ), Center for Genomics and Personalized Medicine
  • ,
  • Veerle Paternoster, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Department of Biomedicine and Centre for Integrative Sequencing (iSEQ), Aarhus University, Centre for Integrative Sequencing (iSEQ), Center for Genomics and Personalized Medicine
  • ,
  • Tue Fryland
  • Johan Palmfeldt
  • Kim Fejgin, H. Lundbeck A/S, Denmark
  • Arne Mørk, H. Lundbeck A/S, Denmark
  • Mette Nyegaard
  • Bente Pakkenberg, Bispebjerg Movement Disorder Biobank, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen
  • ,
  • Michael Didriksen, H. Lundbeck A/S, Denmark
  • Jens R Nyengaard
  • Gregers Wegener
  • Ole Mors
  • Jane H Christensen
  • Anders D Børglum

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.

Original languageEnglish
JournalTranslational Psychiatry
Volume10
Issue1
Pages (from-to)239
ISSN2158-3188
DOIs
Publication statusPublished - 17 Jul 2020

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