SAP97 rs3915512 Polymorphism Affects the Neurocognition of Schizophrenic Patients: A Genetic Neuroimaging Study

Xu, Xusan; He, Bin; Lin, Zhongqiu; Wang, Xiaoxia; Yin, Jingwen; Luo, Xudong; Luo, Shucun; Liang, Chunmei; Wen, Xin; Xiong, Susu; Zhu, Dongjian; Fu, Jiawu; Lv, Dong; Dai, Zhongmin; Lin, Juda; Li, You; Chen, Wubiao; Luo, Zhen; Wang, Yajun; Ma, Guoda

doi:10.3389/fgene.2020.572414

Cited by 7 publications

(3 citation statements)

References 31 publications

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“…Taken together, these results are puzzling since it has been demonstrated a pivotal role of this synaptic element in regulating the trafficking of the glutamate AMPA receptors, whose expression, and function have been reported to be altered in SCZ [35]. In this regard, compelling evidence, including genetic-imaging studies, suggests that genetic variants of the DLG1 gene are functionally linked to abnormal cognitive patterns in SCZ patients [36][37][38][39][40]. In particular, Xu and colleagues reported that SAP97 rs3915512 polymorphism in patients with first-episode schizophrenia was associated with low structural and functional connectivity within the orbitofrontal-striatal-thalamic circuitry [41].…”

Section: Discussionmentioning

confidence: 99%

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

Maio

Rosa

Pelucchi

et al. 2022

IJMS

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Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post-mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson’s and Alzheimer’s disease. Interestingly, also in Parkinson’s disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.

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Section: Discussionmentioning

confidence: 99%

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

Maio

Rosa

Pelucchi

et al. 2022

IJMS

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“…The genomic DNA of all participants was extracted from EDTA-treated peripheral blood using the Tiangen DNA Isolation Kit (Tiangen Biotech, Beijing, China). As described before [ 17 ], the SAP97 rs3915512 polymorphism was examined using the improved multiplex ligation detection reaction (imLDR) technique (Genesky Biotech, Shanghai, China). The polymerase chain reaction (PCR) primers used for the rs3915512 polymorphism were as follows: rs3915512 forward primer: 5’-TGTTCAGGTGCATCAAGTGGTCTTTACA-3’, rs3915512 reverse primer: 5’-CTTCAGTAACTTCCAGTCAGATATGGCCT-3’.…”

Section: Methodsmentioning

confidence: 99%

Genetic contribution of synapse-associated protein 97 to cerebellar functional connectivity changes in first-episode schizophrenia

Xu,

Luo,

Wang

et al. 2023

BMC Psychiatry

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Our previous study data suggested that the synapse-associated protein 97 (SAP97) rs3915512 polymorphism is significantly related to clinical performance in schizophrenia. The cerebellum exhibits abundant expression of SAP97, which is involved with negative symptoms, cognition and emotion in schizophrenia. As functional dysconnectivity with the cortical-subcortical-cerebellar circuitry has been widely shown in patients with schizophrenia, cortical-subcortical-cerebellar dysconnectivity can therefore be considered a possible intermediate phenotype that connects risk genes with schizophrenia. In this study, resting-state functional magnetic resonance imaging (fMRI) was applied to evaluate whether the SAP97 rs3915512 polymorphism changes cortical/subcortical-cerebellar resting-state functional connectivity (RSFC) in 104 Han Chinese subjects (52 first-episode schizophrenia (FES) patients and 52 matched healthy controls (HCs)). To examine RSFC between cortical/subcortical regions and the cerebellum, a ROI (region of interest)-wise functional connectivity analysis was conducted. The association between abnormal cortical/subcortical-cerebellar connectivity and clinical manifestation was further assessed in FES patients with different genotypes. The interactive effect of disease and genotype on RSFC was found between the frontal gyrus (rectus) and cerebellum. A positive correlation was suggested between RSFC in the cerebellum and the hostility scores in FES patients with the A allele, and no correlation was found in FES patients with the TT genotype. The current findings identified that SAP97 may be involved in the process of mental symptoms in FES patients via cerebellar connectivity depending on the rs3915512 polymorphism genotype.

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“…Both the ANK2 and ANK3 genes show strong associations with SZ ( Luoni et al, 2016 ; Stevens and Rasband, 2021 ). Second, NrCAM is also associated with SAP97 ( Dirks et al, 2006 ), an adapter for glutamate receptors ( Waites et al, 2009 ; Li et al, 2011 ); SAP97 is associated with SZ, in particular with neurocognitive dysfunctions ( Uezato et al, 2017 ; Xu et al, 2018 , 2020 , 2021 ), and SZ-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory ( Kay et al, 2022 ). Third, NrCAM is expressed in cortical astrocytes and neurons and forms perisynaptic contacts at inhibitory synapses.…”

Section: Introductionmentioning

confidence: 99%

NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia

Buhusi,

Brown,

Buhusi

2024

Front. Behav. Neurosci.

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The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan, from axonal growth and guidance to spine and synaptic pruning, to organization of proteins at the nodes of Ranvier. NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia. Here we investigated the effects of chronic unpredictable stress on latent inhibition, a measure of selective attention and learning which shows alterations in schizophrenia, in NrCAM knockout (KO) mice and their wild-type littermate controls (WT). Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001). However, following chronic unpredictable stress, WT mice (p = 0.002), but not NrCAM KO mice (F < 1), expressed latent inhibition. Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001), a single hit by stress in Acb-shell (p = 0.031), a dual hit stress x genotype in mOFC (p = 0.008), vOFC (p = 0.020), and Acb-core (p = 0.032), and no effect in PrL cortex (p > 0.141). These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

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SAP97 rs3915512 Polymorphism Affects the Neurocognition of Schizophrenic Patients: A Genetic Neuroimaging Study

Cited by 7 publications

References 31 publications

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

Genetic contribution of synapse-associated protein 97 to cerebellar functional connectivity changes in first-episode schizophrenia

NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia

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