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Molecular Neurobiology

, Volume 54, Issue 3, pp 1699–1709 | Cite as

Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice—Potential Link to Cognitive Impairment in Schizophrenia

  • Yong Chen
  • Sookhee Bang
  • Mary F. McMullen
  • Hala Kazi
  • Konrad Talbot
  • Mei-Xuan Ho
  • Greg Carlson
  • Steven E. Arnold
  • Wei-Yi OngEmail author
  • Sangwon F. KimEmail author
Article

Abstract

Schizophrenia is a chronic debilitating neuropsychiatric disorder that affects about 1 % of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of the Research Domain Constructs (RDoC) associated with cognition and is significantly reduced in the brain of schizophrenia patients. To further understand the molecular underpinnings of pathogenesis of schizophrenia, we have performed microarray analyses of the hippocampi from dysbindin knockout mice, and found that genes involved in the lipogenic pathway are suppressed. Moreover, we discovered that maturation of a master transcriptional regulator for lipid synthesis, sterol regulatory element binding protein-1 (SREBP1) is induced by neuronal activity, and is required for induction of the immediate early gene ARC (activity-regulated cytoskeleton-associated protein), necessary for synaptic plasticity and memory. We found that nuclear SREBP1 is dramatically reduced in dysbindin-1 knockout mice and postmortem brain tissues from human patients with schizophrenia. Furthermore, activity-dependent maturation of SREBP1 as well as ARC expression were attenuated in dysbindin-1 knockout mice, and these deficits were restored by an atypical antipsychotic drug, clozapine. Together, results indicate an important role of dysbindin-1 in neuronal activity induced SREBP1 and ARC, which could be related to cognitive deficits in schizophrenia.

Keywords

Lipid synthesis SREBP Dysbindin Cognition Antipsychotics NMDA PUFA DHA ATP Synaptic Plasticity Cerebral Cortex Neurons 

Notes

Acknowledgments

We thank Ms. Hui-Jen Lye and Ms. Sau-Yeen Loke for help with microarray analyses. This work was supported by the National Research Foundation, National Medical Research Council and National University Health System, Singapore (WYO) and by HD026979, MH079614, and DK084336 (SFK).

Supplementary material

12035_2016_9773_MOESM1_ESM.docx (17 kb)
ESM 1 (DOCX 17 kb)
12035_2016_9773_MOESM2_ESM.docx (28 kb)
ESM 2 (DOCX 27 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yong Chen
    • 1
  • Sookhee Bang
    • 1
  • Mary F. McMullen
    • 1
  • Hala Kazi
    • 1
  • Konrad Talbot
    • 1
  • Mei-Xuan Ho
    • 3
  • Greg Carlson
    • 1
  • Steven E. Arnold
    • 1
  • Wei-Yi Ong
    • 3
    Email author
  • Sangwon F. Kim
    • 1
    • 2
    Email author
  1. 1.Department of Psychiatry, Center for Neurobiology and BehaviorPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Systems Pharmacology and Translational TherapeuticsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Anatomy and Neurobiology Research ProgrammeNational University of SingaporeSingaporeSingapore

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