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 deliberating neuropsychiatric disorder that affects about 1% of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of 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 lipogenic pathway are suppressed. Moreover, we uncovered 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 the induction of the immediate early gene protein ARC (activity-regulated cytoskeleton-associated protein), necessary for synaptic plasticity and memory. We revealed that nuclear SREBP1 is dramatically reduced in dysbindin-1 knockout mice and postmortem brain tissues from human schizophrenia patients. Furthermore, activity-dependent maturation of SREBP1 as well as ARC expression were attenuated in the dysbindin-1 knockout mice, and these deficits were restored by the 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.

Six Years of Research on the National Institute of Mental Health’s Research Domain Criteria (RDoC) Initiative: A Systematic Review

“…It was shown that scratching behavior, an indicator of negative arousal, exhibited a sex-specific association with both AVPR1A genotype, a gene related to mammalian social behavior, and brain morphometry in regions associated with this gene. Although only three studies (Chen et al, 2016; Kondo et al, 2016; Latzman et al, 2016) employed non-human mammals in their research, they highlight how animal research can contribute to the understanding of species-general elements within the RDoC matrix.…”

“…Rather than focusing on an RDoC construct , one study examined a single element of the Perception construct within the Cognitive Systems matrix. Chen et al ( 2016 ) explored the relationship between the expression of the dysbindin protein, found in neural tissue, and disturbances in the regulation of lipid synthesis and synaptic plasticity. A reduction of sterol regulatory element binding protein-1 (SREBP1), a transcriptional regulator for lipid synthesis, was found in both deceased patients with schizophrenia and dysbindin-1 knockout mice.…”

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

“…Expression of SREBP1, a sterol regulatory element binding protein (SREBP) that regulates the expression of genes implicated in biosynthesis of fatty acids, cholesterol, triglycerides, and phospholipids, is reduced in sdy/B6 mice and in schizophrenia patients; activation of SREBP1 and Arc, a protein implicated in memory and cognition, is reduced in sdy/B6 mice and both of these deficits were restored by treatment with clozapine, suggesting a link with cognitive dysfunction (Chen et al, 2016).…”

Schizophrenia: What’s Arc Got to Do with It?

“…Again, deletions in a subset of genes belonging to the Arc complex were significantly enriched in patients with schizophrenia (Marshall et al, 2017 ). Finally, different mouse models relevant to schizophrenia show reduced Arc expression, which is instead not evident in mouse models relevant to other psychiatric disorders such as ADHD or bipolar disorders (Matsuo et al, 2009 ; Takao et al, 2013 ; Takagi et al, 2015 ; Managò et al, 2016 ; Chen et al, 2017 ; Mereu et al, 2017 ). This might suggest that the Arc pathway may serve as a hub that functionally links numerous schizophrenia risk-related factors.…”