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

Biol Psychiatry. 2017 Jul 1;82(1):62-76. doi: 10.1016/j.biopsych.2016.08.037. Epub 2016 Sep 15.


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 [Chrm4)], 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.

Keywords: BRD1; Behavior; Cyclic AMP response element-binding protein (CREB); DARPP-32 signaling; Electrophysiology; Knockout mouse; Monoaminergic neurotransmission; RNAseq; Schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Animals, Genetically Modified / genetics
  • Behavior, Animal / physiology*
  • Corpus Striatum / metabolism
  • Dopamine / metabolism
  • Gene Expression / genetics*
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / physiology*
  • Histones / metabolism
  • Interneurons / physiology
  • Mice
  • Schizophrenia / genetics*
  • Serotonin / metabolism
  • Synaptic Transmission / genetics*


  • BRD1 protein, mouse
  • Histones
  • Serotonin
  • Histone Acetyltransferases
  • Dopamine