The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice

• Published in: Biological psychiatry (1969) Vol. 82; no. 1; pp. 62 - 76
• Main Authors: Qvist, Per, Christensen, Jane Hvarregaard, Vardya, Irina, Rajkumar, Anto Praveen, Mørk, Arne, Paternoster, Veerle, Füchtbauer, Ernst-Martin, Pallesen, Jonatan, Fryland, Tue, Dyrvig, Mads, Hauberg, Mads Engel, Lundsberg, Birgitte, Fejgin, Kim, Nyegaard, Mette, Jensen, Kimmo, Nyengaard, Jens Randel, Mors, Ole, Didriksen, Michael, Børglum, Anders Dupont
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017
• Subjects: Acetylation; Animals; Animals, Genetically Modified - genetics; Behavior; Behavior, Animal - physiology; BRD1; Corpus Striatum - metabolism; Cyclic AMP response element-binding protein (CREB); DARPP-32 signaling; Dopamine - metabolism; Electrophysiology; Gene Expression - genetics; Histone Acetyltransferases - genetics; Histone Acetyltransferases - physiology; Histones - metabolism; Interneurons - physiology; Knockout mouse; Mice; Monoaminergic neurotransmission; Psychiatry; RNAseq; Schizophrenia; Schizophrenia - genetics; Serotonin - metabolism; Synaptic Transmission - genetics; BRD1; Monoaminergic neurotransmission; Knockout mouse; DARPP-32 signaling; Electrophysiology; Schizophrenia; Behavior; Cyclic AMP response element-binding protein (CREB); RNAseq
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2016.08.037

Abstract Background The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. Methods This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1+/− mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters. Results Brd1+/− mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1+/− and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [ Cacna1c and Cacnb2 ], cholinergic muscarinic receptor 4 [C hrm4 )], dopamine receptor D2 [ Drd2 ], and transcription factor 4 [ Tcf4 ]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]). Conclusions Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.