Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1genes

Sacchetti, Emilio; Scassellati, Catia; Minelli, Alessandra; Valsecchi, Paolo; Bonvicini, Cristian; Pasqualetti, Patrizio; Galluzzo, Alessandro; Pioli, Rosaria; Gennarelli, Massimo

doi:10.1186/1471-2350-14-33

Cited by 25 publications

(23 citation statements)

References 39 publications

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“…Evidence supports that both genetic (Greenwood et al, 2013;Kiyomi Ota et al, 2013;Sacchetti et al, 2013) and environmental factors (Brown et al, 2000;Gerard and Houston, 1953;Kendell and Kemp, 1989) contribute to the development of the disease. The dopamine (Snyder, 1976;van Rossum, 1966), glutamate (Javitt and Zukin, 1991), and various genetic (Craddock et al, 2007;McClellan et al, 2007) and environmental (Brown et al, 2000;Cannon et al, 2002;Cantor-Graae, 2007) hypotheses of schizophrenia help explain phenomena observed in patients; however, it is a combination of some, or all, of these factors that likely leads to schizophrenia pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

Perez

Aguilar

Neary

et al. 2015

Neuropsychopharmacol

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Both environmental and genetic factors contribute to schizophrenia; however, the exact etiology of this disorder is not known. Animal models are utilized to better understand the mechanisms associated with neuropsychiatric diseases, including schizophrenia. One of these involves gestational administration of methylazoxymethanol acetate (MAM) to induce a developmental disruption, which in turn produces a schizophrenia-like phenotype in post-pubertal rats. The mechanisms by which MAM produces this phenotype are not clear; however, we now demonstrate that MAM induces differential DNA methylation, which may be heritable. Here we demonstrate that a subset of both second (F2) and third (F3) filial generations of MAM-treated rats displays a schizophrenia-like phenotype and hypermethylation of the transcription factor, Sp5. Specifically, ventral tegmental area of dopamine neuron activity was examined using electrophysiology as a correlate for the dopamine hyperfunction thought to underlie psychosis in patients. Interestingly, only a subset of F2 and F3 MAM rats exhibited increases in dopamine neuron population activity, indicating that this may be a unique model with a susceptibility to develop a schizophrenia-like phenotype. An increase in dopamine system function in rodent models has been previously associated with decreases in hippocampal GABAergic transmission. In line with these observations, we found a significant correlation between hippocampal parvalbumin expression and dopamine neuron activity in F2 rats. These data therefore provide evidence that offspring born from MAMtreated rats possess a susceptibility to develop aspects of a schizophrenia-like phenotype and may provide a useful tool to investigate geneenvironment interactions.

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Section: Introductionmentioning

confidence: 99%

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

Perez

Aguilar

Neary

et al. 2015

Neuropsychopharmacol

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“…Specific haplotypes of this gene have been associated with schizophrenia (9,(13)(14)(15)(16)(17), and the expression of its mRNA has been found to be reduced in the hippocampus of human schizophrenia patients (8). Because CNA␥ has long been thought to be a testis-specific protein (7), there has been no reported information on functions of CNA␥ relevant to its role in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…A mouse with forebrain-specific knockout of the calcineurin regulatory subunit, calcineurin B1 (CNB1), has a behavioral phenotype that recapitulates several of the endophenotypes characteristic of schizophrenia, including a selective disruption of working memory (11,12). Moreover, genetic and potential epigenetic variation in the PPP3CC gene has been reported to be associated with schizophrenia or its cognitive impairments in specific population-based or genome-wide methylation studies, respectively (9,(13)(14)(15)(16)(17)(18), although genetic association has not been reported from largescale, controlled genome-wide association studies performed to date. Finally, a reduction in PPP3CC mRNA levels was observed in the hippocampus of schizophrenia patients (8).…”

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confidence: 99%

Calcineurin Aγ is a Functional Phosphatase That Modulates Synaptic Vesicle Endocytosis

Cottrell

Kyung

et al. 2016

Journal of Biological Chemistry

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Variation in PPP3CC, the gene that encodes the ␥ isoform of the calcineurin catalytic subunit, has been reported to be associated with schizophrenia. Because of its low expression level in most tissues, there has been little research devoted to the specific function of the calcineurin A␥ (CNA␥) versus the calcineurin A␣ (CNA␣) and calcineurin A␤ (CNA␤) catalytic isoforms. Consequently, we have a limited understanding of the role of altered CNA␥ function in psychiatric disease. In this study, we demonstrate that CNA␥ is present in the rodent and human brain and dephosphorylates a presynaptic substrate of calcineurin. Through a combination of immunocytochemistry and immuno-EM, we further show that CNA␥ is localized to presynaptic terminals in hippocampal neurons. Critically, we demonstrate that RNAi-mediated knockdown of CNA␥ leads to a disruption of synaptic vesicle cycling in cultured rat hippocampal neurons. These data indicate that CNA␥ regulates a critical aspect of synaptic vesicle cycling and suggest that variation in PPP3CC may contribute to psychiatric disease by altering presynaptic function.

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“…Calcineurin (Cn) is a calcium-dependent protein phosphatase and has been implicated in synaptic plasticity 50 . CN has been reported to be associated with schizophrenia 51–53 , and altered expression of calcineurin has been observed in the postmortem brains of patients with schizophrenia 54,55 . Forebrain-specific Cn KO mice exhibit behavioral and cognitive abnormalities related to schizophrenia 35,36 .…”

Section: Methodsmentioning

confidence: 99%

Lower brain pH as a shared endophenotype of psychotic disorders

Hagihara

Catts

Katayama

et al. 2016

Preprint

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37Lower pH is a well-replicated finding in the postmortem brains of patients with schizophrenia and 38 bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding 39 reflects a primary feature of the diseases or is a result of confounding factors such as medication, 40 postmortem interval, and agonal state. To date, systematic investigation of brain pH has not been 41 undertaken using animal models, which can be studied without confounds inherent in human studies. 42In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar 43 disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then 44utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis 45 that lower brain pH exists in these brains compared to controls due to the underlying 46 pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in 47 brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific 48 calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and 49 one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same 50 postmortem interval and agonal state at death. Upon postmortem examination, we observed 51 significantly lower pH and higher lactate levels in the brains of model mice relative to controls. 52There was a significant negative correlation between pH and lactate levels. These results suggest 53 that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather 54 than mere artifacts. 55 56. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/083550 doi: bioRxiv preprint first posted online Oct. 26, 2016; 4 Introduction 57 Schizophrenia, bipolar disorder, and autism spectrum disorders (ASD) are highly heritable 58 psychiatric conditions, with clinical features transcending diagnostic categories 1,2 . Accumulating 59 evidence indicates that some genetic influences [3][4][5][6] , gene expression abnormalities 7,8 , and neuronal 60 dysfunctions 9,10 associated with these conditions overlap, suggesting a common underlying 61 biological basis. However, the shared neurobiological alterations among the three conditions remain 62 largely unknown. 63 64A number of postmortem studies have indicated that pH is lower in the brains of patients with 65 schizophrenia and bipolar disorder 8,[11][12][13][14][15][16][17][18][19] . Lower brain pH has also been observed in patients with 66 ASD 20 . In general, pH balance is considered critical for maintaining optimal health, and low pH has 67 been associated with a number of somatic disorders [21][22][23] . Therefore, it is reasonable to assume that 68 lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of 6...

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Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1genes

Cited by 25 publications

References 39 publications

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

Calcineurin Aγ is a Functional Phosphatase That Modulates Synaptic Vesicle Endocytosis

Lower brain pH as a shared endophenotype of psychotic disorders

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