Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia

Karlsgodt, Katherine H.; Sun, Daqiang; Jimenez, Amy M.; Lutkenhoff, Evan S.; Willhite, Rachael; Erp, Theo G.M. van; Cannon, Tyrone D.

doi:10.1017/s095457940800062x

Cited by 129 publications

(92 citation statements)

References 305 publications

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“…First, we find that cortical transcriptome is organized into modules of coexpressed genes, and that significant preservation of coexpression relationships exists in normal and disease states, suggesting that major perturbations in gene connectivity do not distinguish schizophrenia from controls on a molecular level. Schizophrenia has been thought of as a disorder of reduced functional and structural cortical connectivity (Karlsgodt et al 2008). Much evidence for this theory comes from magnetic resonance imaging studies showing abnormal functional connectivity between prefrontal Figure 3.…”

Section: Discussionmentioning

confidence: 99%

Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia

Torkamani

Dean²,

Schork³

et al. 2010

Genome Res.

126

136

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We performed integrated gene coexpression network analysis on two large microarray-based brain gene expression data sets generated from the prefrontal cortex obtained post-mortem from 101 subjects, 47 subjects with schizophrenia and 54 normal control subjects, ranging in age from 19 to 81 years. Twenty-eight modules of coexpressed genes with functional interpretations were detected in both normal subjects and those with schizophrenia. Significant overlap of “case” and “control” module composition was observed, indicating that extensive differences in underlying molecular connectivity are not likely driving pathology in schizophrenia. Modules of coexpressed genes were characterized according to disease association, cell type specificity, and the effects of aging. We find that genes with altered expression in schizophrenia clustered into distinct coexpression networks and that these were associated primarily with neurons. We further identified a robust effect of age on gene expression modules that differentiates normal subjects from those with schizophrenia. In particular, we report that normal age-related decreases in genes related to central nervous system developmental processes, including neurite outgrowth, neuronal differentiation, and dopamine-related cellular signaling, do not occur in subjects with schizophrenia during the aging process. Extrapolating these findings to earlier stages of development supports the concept that schizophrenia pathogenesis begins early in life and is associated with a failure of normal decreases in developmental-related gene expression. These findings provide a novel mechanism for the “developmental” hypothesis of schizophrenia on a molecular level.

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Section: Discussionmentioning

confidence: 99%

Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia

Torkamani

Dean²,

Schork³

et al. 2010

Genome Res.

126

136

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show abstract

“…Recently, these ideas have been reconsidered to explain the pathology of schizophrenia. The current hypothesis is that the pathological phenotype may be due to an enhanced rate of synaptic pruning, resulting in excessive loss of neuronal connectivity in the course of adolescent brain development accompanied with cognitive deficits (199), thus suggesting an entirely new pharmacological approach to schizophrenia based upon synapse stabilization factors.…”

Section: Supramolecular Morphogenesis Of the Synapsementioning

confidence: 99%

Allosteric Receptors: From Electric Organ to Cognition

Changeux

2010

Annu. Rev. Pharmacol. Toxicol.

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This autobiography covers the past 50 years beginning with the development of the concept of allosteric proteins and its application to pharmacological receptors. It continues with the identification of the nicotinic acetylcholine receptor, the discovery of its molecular organization, the structure of the acetylcholine-binding site and of the ion channel, and the demonstration of its allosteric transitions. The article then traces the origins of the concept of allosteric modulator and its consequences in pharmacology. It proceeds with the theory of selective stabilization of synapses and with experimental studies carried out on the contribution of the nicotinic receptor in the morphogenesis of the neuromuscular junction. The knowledge acquired with the nicotinic receptor is further exploited to reach higher levels of brain organization, and the contribution of nicotinic receptors to the action of nicotine on reward and cognition is explored, in particular, using a novel experimental strategy that combines nicotinic receptor genes knock-out and stereotaxic gene re-expression. Theoretical models of cognitive functions are proposed that link the molecular to the cognitive level. The report ends with a discussion on nicotinic receptors and the pharmacology of the future.

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“…Cognitive deficits are a core feature in SCZ [109], and brain structural changes such as reduced hippocampal and cortical volume [110], the extracellular matrix (ECM) abnormalities [111], as well as reduced cortical thickness [112] have been reported in SCZ patients.…”

Section: Schizophrenia and Brain Structurementioning

confidence: 99%

Are There Schizophrenia Genetic Markers and Mutations? A Systematic Review and Meta-Analyses

Cardoso¹,

Nascimento²,

Bernardo³

et al. 2017

Health

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Background: Schizophrenia is a severe psychiatric disorder with a complex genetic factor determining its disease onset. Nevertheless, it is not clear in this mental disorder. Objective: To conduct a systematic review of articles regarding the genetic markers and mutations in schizophrenia. Methods: A systematic review of articles on genetic markers and mutations in schizophrenia, published from January 1, 2011, to September 7, 2015, on SCOPUS database was carried out. Search terms were "Genetic markers", "Mutation", and "Schizophrenia". Results: Of the 527 retrieved studies, 31 met the eligibility criteria. Genetic polymorphism, Immune-associated genes, TCF4 and ZNF804A association with microRNA, Neuregulin gene, Chromosome 13q32 and 11p15.4, genes involved in glutamatergic via schizophrenia and brain structure, appeared to be associated with the origin of schizophrenia. Conclusion: Some studies show genes involved in several pathways leading to the disease pathogenesis such as that one related with the dopaminergic and immune system, or rare alleles. Some genes present no involvement in the etiology of this mental disorder. These findings clarify the genetic complexity of schizophrenia and affirm that together, the genes have an overall effect greater than the sum of the individual effect of each gene. KeywordsSchizophrenia, Genetic Markers, Mutations, Systematic Review How to cite this paper: Cardoso, M.A.B.S., do Nascimento, T

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Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia

Cited by 129 publications

References 305 publications

Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia

Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia

Allosteric Receptors: From Electric Organ to Cognition

Are There Schizophrenia Genetic Markers and Mutations? A Systematic Review and Meta-Analyses

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