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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that consistent structural changes exist in the hippocampi of schizophrenic patients. These alterations are characterized by a significant degree of disorientation of the hippocampal pyramidal cells when compared with age-matched nonschizophrenic controls. The degree of neuronal disorientation seems to correlate positively with the severity of the clinical picture. A hypothesis on the pathogenesis of this process, suggested in an earlier article, is extended here. Putative maternal infection with one of several neuraminidase-bearing viruses, especially during the second trimester of pregnancy, may severely affect the migration of primitive neurons into the primordial hippocampus. The "neuraminidase effect," expressed through alteration of the normal sequential patterns of N-CAM (neuronal-cell adhesion molecule) maturation, may result in the cellular disarray we have noted. This alteration may prove useful as a cell marker for schizophrenia, even though its actual relation to clinical symptomatology has still to be evaluated. Genetic factors also are believed to be involved, perhaps in the form of certain patterns of reduced immunocompetence, which might render the mother more susceptible to viral infection.
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PMID:Schizophrenia and the hippocampus: the embryological hypothesis extended. 343 7

The KSV model of the schizophrenias proposes that up to 70% of schizophrenics have a pathogenic allele, or abnormal expression, of the KALIG-1 gene which is located at Xp22.3. This gene encodes a nerve-cell adhesion molecule (N-CAM) like protein, and is deleted in 66% of patients with Kallmann's syndrome, anosmia with secondary hypogonadism. Although superficially distinct, the schizophrenias and Kallmann's syndrome show numerous parallel trait defects which occur with a similar sex distribution. These defects are usually more profound in Kallmann's syndrome. Occasionally, Kallmann's patients exhibit additional defects, such as ichthyosis, which are due to the further deletion or translocation of adjacent genes. Since schizophrenics exhibit virtually all known trait defects in Kallmann's except these, it suggests that the aberrant genes are defective, but not deleted in schizophrenia. It also appears that compensatory mechanisms, involving serine proteases, are active in schizophrenia, which largely preserve fertility, but at the expense of an increased vulnerability to develop a psychosis by an episodic disruption of the blood-CSF barrier. Consequently, schizophrenia is rare in Kallmann's patients, while most schizophrenics are capable of reproduction.
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PMID:The Kallmann's syndrome variant (KSV) model of the schizophrenias. 846 Dec 65

While schizophrenia has a genetic component, its pathogenesis is unknown. Abnormal concentrations of two cell recognition molecules (CRMs), neural-cell adhesion molecule (N-CAM) and L1 antigen have been described in the cerebrospinal fluid (CSF) of patients with schizophrenia. Studies of monozygotic twins discordant for schizophrenia may help separate genetic and environmental contributions to the disease. In the present study of monozygotic twins discordant for schizophrenia, the affected twins had increased N-CAM and decreased L1 antigen in their CSF. Non-affected twins were not different from normals. Although processes related to genetic instability cannot be entirely ruled out, these results suggest that these abnormalities are not a part of the genetic predisposition to become schizophrenic. Thus the changes in N-CAM and L1 antigen may reflect either the events which precipitated the onset of schizophrenia, or events which are associated with the experience of having the disease.
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PMID:Monozygotic twins discordant for schizophrenia are discordant for N-CAM and L1 in CSF. 909 80

L1 and Thy-1 are members of the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs) that are vital for normal neural development. Abnormalities in CAM expression could lead to the histological abnormalities that have previously been described in the frontal cortex of patients with schizophrenia. A postmortem immunohistochemical study of L1 and Thy-1 in the normal human prefrontal cortex revealed positive immunostaining of axons in all layers of the cortex. Quantifying the intensity of immunostaining in the prefrontal cortex of patients with schizophrenia, bipolar disorder and depression failed to reveal any significant differences when compared to that of normal controls.
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PMID:Immunohistochemical localization of the cell adhesion molecules Thy-1 and L1 in the human prefrontal cortex patients with schizophrenia, bipolar disorder, and depression. 1008 8

An abnormality in neurodevelopment is one of the most robust etiologic hypotheses in schizophrenia (SZ). There is also strong evidence that genetic factors may influence abnormal neurodevelopment in the disease. The present study evaluated in SZ patients, whose brain structural data had been obtained with magnetic resonance imaging (MRI), the possible association between structural brain measures, and 32 DNA polymorphisms, located in 30 genes related to neurogenesis and brain development. DNA was extracted from peripheral blood cells of 25 patients with schizophrenia, genotyping was performed using diverse procedures, and putative associations were evaluated by standard statistical methods (using the software Statistical Package for Social Sciences - SPSS) with a modified Bonferroni adjustment. For reelin (RELN), a protease that guides neurons in the developing brain and underlies neurotransmission and synaptic plasticity in adults, an association was found for a non-synonymous polymorphism (Val997Leu) with left and right ventricular enlargement. A putative association was also found between protocadherin 12 (PCDH12), a cell adhesion molecule involved in axonal guidance and synaptic specificity, and cortical folding (asymmetry coefficient of gyrification index). Although our results are preliminary, due to the small number of individuals analyzed, such an approach could reveal new candidate genes implicated in anomalous neurodevelopment in schizophrenia.
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PMID:Polymorphisms in genes involved in neurodevelopment may be associated with altered brain morphology in schizophrenia: preliminary evidence. 1905 71

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the 'enrichment' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.
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PMID:Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. 2015 12

Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.
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PMID:Confirmed rare copy number variants implicate novel genes in schizophrenia. 2029

The major mental disorders, schizophrenia and bipolar disorder are substantially heritable. Recent genomic studies have identified a small number of common and rare risk genes contributing to both disorders and support epidemiological evidence that genetic susceptibility overlaps between them. Prompted by the question of whether risk genes cluster in specific molecular pathways or implicate discrete mechanisms we and others have developed hypothesis-free methods of investigating genome-wide association datasets at a pathway-level. The application of our method to the 212 experimentally-derived pathways in the Kyoto Encycolpaedia of Genes and Genomes (KEGG) database identified significant association between the cell adhesion molecule (CAM) pathway and both schizophrenia and bipolar disorder susceptibility across three GWAS datasets. Interestingly, a similar approach applied to an autistic spectrum disorders (ASDs) sample identified a similar pathway and involved many of the same genes. Disruption of a number of these genes (including NRXN1, CNTNAP2 and CASK) are known to cause diverse neurodevelopmental brain disorder phenotypes including schizophenia, autism, learning disability and specific language disorder. Taken together these studies bring the CAM pathway sharply into focus for more comprehensive DNA sequencing to identify the critical genes, and investigate their relationships and interaction with environmental risk factors in the expression of many seemingly different neurodevelopmental disorders.
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PMID:Neuronal cell adhesion genes: Key players in risk for schizophrenia, bipolar disorder and other neurodevelopmental brain disorders? 2057 49

Homophilic interaction of the L1 family of cell adhesion molecules plays a pivotal role in regulating neurite outgrowth and neural cell networking in vivo. Functional defects in L1 family members are associated with neurological disorders such as X-linked mental retardation, multiple sclerosis, low-IQ syndrome, developmental delay, and schizophrenia. Various human tumors with poor prognosis also implicate the role of L1, a representative member of the L1 family of cell adhesion molecules, and ectopic expression of L1 in fibroblastic cells induces metastasis-associated gene expression. Previous studies on L1 homologs indicated that four N-terminal immunoglobulin-like domains form a horseshoe-like structure that mediates homophilic interactions. Various models including the zipper, domain-swap, and symmetry-related models are proposed to be involved in structural mechanism of homophilic interaction of the L1 family members. Recently, cryo-electron tomography of L1 and crystal structure studies of neurofascin, an L1 family protein, have been performed. This review focuses on recent discoveries of different models and describes the possible structural mechanisms of homophilic interactions of L1 family members. Understanding structural mechanisms of homophilic interactions in various cell adhesion proteins should aid the development of therapeutic strategies for L1 family cell adhesion molecule-associated diseases.
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PMID:Homophilic interaction of the L1 family of cell adhesion molecules. 2257 11

Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior.
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PMID:Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. 2345 Nov 1


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