Rethinking schizophrenia in the context of normal neurodevelopment

Catts, Vibeke S.; Fung, Samantha J.; Long, Leonora E.; Joshi, Dipesh; Vercammen, Ans; Allen, Katherine M.; Fillman, Stu G.; Rothmond, Debora A.; Sinclair, Duncan; Tiwari, Yash; Tsai, Shan-Yuan; Weickert, Thomas; Weickert, Cynthia Shannon

doi:10.3389/fncel.2013.00060

Cited by 169 publications

(140 citation statements)

References 379 publications

(506 reference statements)

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“…This unique cognitive function depends on brain maturation from childhood to adulthood in humans (Lebel et al, 2008;Catts et al, 2013). Therefore, it is likely that immaturity negatively impacts high-order cognition acquired at each developmental stage.…”

Section: Social Cognitive Deficits In Asdmentioning

confidence: 99%

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Nakagawa¹,

Chiba²

2016

Journal of Pharmacology and Experimental Therapeutics

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Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset.

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Section: Social Cognitive Deficits In Asdmentioning

confidence: 99%

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Nakagawa¹,

Chiba²

2016

Journal of Pharmacology and Experimental Therapeutics

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“…Strong research findings indicate that schizophrenia is a complex neurodevelopmental disorder (Fatemi and Folsom 2009;Catts et al 2013). Thus, we investigated how schizophrenia risk genes are expressed during brain development.…”

Section: Expression Of Schizophrenia Risk Genes During Brain Developmentmentioning

confidence: 99%

Integrated Post-GWAS Analysis Sheds New Light on the Disease Mechanisms of Schizophrenia

Lin¹,

Cai²,

Zhang³

et al. 2016

Genetics

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Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization. We identify 132 putative schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are outside the risk regions, likely under regulation of transcriptional regulatory elements contained therein. These putative schizophrenia risk genes are transcriptionally active in both brain and the immune system, and highly enriched among cellular pathways, consistent with leading pathophysiological hypotheses about the pathogenesis of schizophrenia. With their involvement in distinct biological processes, these putative schizophrenia risk genes, with different association strengths, show distinctive temporal expression patterns, and play specific biological roles during brain development.

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“…We specifically examined the dorsolateral prefrontal cortex (DLPFC; BA46) as this region is highly implicated in schizophrenia pathology due to its role in the development of cognitive deficits [2,39]. For the first time, we also assessed the protein levels of novel mGluR5 endogenous regulators, Norbin, Tamalin and Preso1, as markers of mGluR5 localization, trafficking and signaling.…”

Section: Introductionmentioning

confidence: 99%

Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation

et al. 2015

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. (2015). Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation. Acta Neuropathologica, 130 (1), 119-129. Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation AbstractKnockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n = 37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. While mGluR5 mRNA expression was unchanged, mGluR5 protein levels were significantly higher in schizophrenia subjects compared to controls (total: +22 %; dimer: +54 %; p < 0.001). Conversely, mGluR5 regulatory proteins were expressed at lower levels in schizophrenia subjects compared to controls (Norbin −37 %, p < 0.001; Tamalin −30 %, p = 0.084; Preso1 −29 %, p = 0.001). mGluR5 protein was significantly associated with mGluR5 mRNA and mGluR5 endogenous regulators in control subjects, but these associations were lost in schizophrenia subjects. Lastly, there were no associations between protein measures and lifetime antipsychotic history in schizophrenia subjects. To confirm no antipsychotic influence, all proteins were measured in the prefrontal cortex of rats exposed to haloperidol or olanzapine; there were no effects of antipsychotic drug treatment on mGluR5, Norbin, Tamalin or Preso1. The results from our study provide compelling evidence that mGluR5 regulation is altered in schizophrenia, likely contributing to the altered glutamatergic signaling that is associated with the disorder. AbstractKnockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n=37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. Whilst mGluR5 mRNA expression was unc...

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Rethinking schizophrenia in the context of normal neurodevelopment

Cited by 169 publications

References 379 publications

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Integrated Post-GWAS Analysis Sheds New Light on the Disease Mechanisms of Schizophrenia

Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation

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