title: Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia.
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.
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: McMullen
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Hala
authors.initials: H
authors.lastname: Kazi
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Department of Anatomy and Neurobiology Research Programme, National University of Singapore, Singapore, 119260, Singapore.
authors.forename: Mei-Xuan
authors.initials: MX
authors.lastname: Ho
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Carlson
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: Department of Anatomy and Neurobiology Research Programme, National University of Singapore, Singapore, 119260, Singapore. wei_yi_ong@nuhs.edu.sg.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Ong
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. sangwonk@mail.med.upenn.edu.|Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. sangwonk@mail.med.upenn.edu.
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D000074765:Dysbindin / Q000172:deficiency* / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks / Q000502:physiology; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D016716:PC12 Cells; D011897:Random Allocation; D051381:Rats; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D012565:Schizophrenic Psychology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000074765:Dysbindin; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1
keywords: ATP; Antipsychotics; Cerebral Cortex; Cognition; DHA; Dysbindin; Lipid synthesis; NMDA; Neurons; PUFA; SREBP; Synaptic Plasticity