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A Gene Expression Study of the Glutamate-Nitric Oxide Pathway in Schizophrenia

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P.320 A gene expression study of the glutamate-nitric oxide pathway in schizophrenia Kinoshita M1, Candemir E1, Kittel-Schneider S1, Reif, A1 and Freudenberg F1 1Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Translational Psychiatry, University Hospital Frankfurt BACKGROUND RESULTS Neuronal nitric oxide synthase (NOS-I) and its adaptor protein NOS1AP have Table 3. The results of linear regression analyses of NOS1AP expression previously been linked to schizophrenia. NOS1AP binding to NOS-I competes with NOS-I/PSD-95 interaction. Thus, increased NOS1AP expression, which has dPFC HPC Estimate (se) t value p value Estimate (se) t value p value been described in patients with schizophrenia [1] may reduce formation of the Diagnosis 0.0635 (0.043) 1.476 0.141 0.123 (0.089) 1.392 0.165 NOS-I/PSD-95/NMDA receptor complex, which may contribute to the Age of death 0.001 (0.001) 0.992 0.322 0.003 (0.003) 1.168 0.244 pathophysiology of schizophrenia [2]. Functionally, NOS1AP overexpression Gender 0.056(0.043) 1.292 0.197 - - - Brain pH -0.317 (0.079) -4.006 7.54E-05 -0.321 (0.148) -2.166 0.031 impacts on neuronal morphology and spine plasticity [3]. Importantly, NOS1AP Postmortem interval 0.004 (0.001) 3.712 2.40E-04 0.006 (0.002) 2.292 0.023 genetic variants have been associated with several schizophrenia-related endophenotypes [4]. Table 4. The results of χ2-tests AIMS Control Schizophrenia p value* NOS1AP expression higher lower higher lower We aimed to investigate the expression of NOS1, NOS1AP and associated dPFC 86(41.1%) 123(58.9%) 95(62.1%) 58(37.9%) 2.56E-0.4 genes in postmortem dorsolateral prefrontal cortex (dPFC) and hippocampus HPC 75(41.0%) 108(59.0%) 75(64.1%) 42(35.9%) 3.04E-04 (HPC) of schizophrenia patients. *Bonferroni corrected • There was a trend for higher expression of NOS1AP in schizophrenia samples. MATERIALS AND METHODS • In fact, higher frequencies of high NOS1AP levels were found in Data extraction: Access to whole-genome gene expression data of postmortem schizophrenia patients. brain tissues from patients with schizophrenia was obtained through dbGaP [5]. The used dataset contains Illumina® HumanHT-12 v4 mRNA expression data Figure 1. Box plots of glutamate-nitric oxide pathway related genes from HPC (134 schizophrenia and 281 controls) and dPFC (202 schizophrenia separated by NOS1AP expression levels and diagnosis and 347 controls). NOS1AP NOS1 CPE Background correction and normalization: Background correction was used dPFC HPC dPFC HPC dPFC HPC for adjusting the baseline probe signaling levels among probes. Quantile CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ * * * * * normalization followed by log2 transformation was performed after background correction. ”neqc” function of “limma” package in R was used. Sample selection: Control samples whose ages of death were under 17 and/or who had any positive history of antidepressant, mood stabilizer or benzodiazepine use were excluded. Samples with a positive history of cannabinoid or cocaine use were also excluded. Finally, samples with no information about cause of death, smoking, or alcohol, benzodiazepine, nicotine RASD1 DLG1 DLG4 or opiate use were excluded. The cause of death was classified as 1) natural, 2) dPFC HPC dPFC HPC dPFC HPC accidental, 3) suicide and 4) homicide. Table 1 shows the demographic details CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ * * * * * * * of samples after the exclusion. * * * * * Table 1. Demographic details of samples Ethnicity Number of Gender Mean age of Mean brain Mean postmortem (Caucasian/Asian/ samples (males/females) Death (SD) pH (SD) Interval (SD) African/Hispanic) 43.65 6.55 31.45 dPFC 209 147/62 90/111/5/3 (15.38) (0.26) (15.05) Control 42.62 6.54 30.85 HPC 183 129/54 71/106/3/3 (15.08) (0.28) (14.36) GRIN2A GRIA2 SYN1 50.33 6.40 38.53 dPFC 153 94/59 78/70/2/3 dPFC HPC dPFC HPC dPFC HPC (15.31) (0.25) (23.76) Schizophrenia CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ 51.04 6.36 36.69 HPC 117 76/41 48/65/2/2 * (15.91) (0.26) (19.57) * * * * * * * * * * Cause of death Smoking Alcohol use Benzodiazepine use Nicotine use Opiate use (natural/accidential/ (positive/negative) (positive/negative) (positive/negative) (positive/negative) (positive/negative) suicide/homicide) 52/157 12/197 168/13/0/28 0/209 50/159 7/202 47/136 11/172 144/9/0/ 0/183 45/138 6/177 110/43 15/138 103/17/31/2 12/141 72/81 16/137 84/33 12/105 81/10/24/2 7/110 64/53 11/106 Evaluation of potential confounding factors with NOS1AP expression and * p <0.05 after Bonferroni correction the linear regression analyses: Relations of potential confounding factors to NOS1AP expression were evaluated using single linear regression analyses. • NOS1AP, RASD1, DLG1, DLG4, GRIA1 and MAPK14 showed significant The evaluated factors were age of death, gender, ethnicity, brain pH, associations between lower and higher NOS1AP expression group in both postmortem interval, smoking history, alcohol use, cause of death, tissues. benzodiazepine use, nicotine use and opiate use. Age of death, brain pH and • GRIA2, GRIN2A and SYN1 showed the significant associations between the postmortem interval showed the significant relations with NOS1AP expression diagnosis in HPC. in HPC tissues and age of death, gender, brain pH and postmortem interval • GRIN2A in dPFC and GRIA2 and GRIN2B in HPC also showed the significant showed significant relations with NOS1AP expression in dPFC tissues. Linear associations between lower and higher NOS1AP expression group. regression analyses were used to assess the associations of diagnosis with NOS1AP expression. CONCLUSIONS Categorization of samples according to the NOS1AP expression levels: Median levels of NOS1AP expression in dPFC and HPC tissues were • Here we demonstrate that schizophrenia patients showed higher NOS1AP calculated. Samples with higher NOS1AP expression levels were included in expression levels than controls in dPFC and HPC. the higher group and samples with lower NOS1AP expression were categorized • We also demonstrate that genes in the glutamate-nitric oxide pathway may be in the lower group. 2 tests were conducted to compare the frequencies of χ modified by the NOS1AP expression levels. higher and lower samples of schizophrenia and control samples. Evaluation of NOS1AP expression levels: To assess the effect of NOS1AP • These results will be confirmed using postmortem brain tissues of expression level on the other genes which play roles in the glutamate-nitric schizophrenia from a separate cohort. NOS1AP oxide pathway, two-way ANOVAs were conducted with expression • Our results confirm and expand previous findings and may help to further group and diagnosis. Genes selected in this study were presented in table 2. All understand the molecular mechanisms contributing to schizophrenia and may statistical analyses were conducted by R ver. 3.2.3. eventually contribute to the development of targeted treatment strategies. Table 2. Glutamate-nitric oxide pathway related genes analysed in this study DISCLOSURE Genes Official full names Genes Official full names This study has been supported in part by the DFG (FR3420/2-2 to FF) and The Japanese Society of Clinical NOS1 Nitric oxide synthase 1 MAPK14 Mitogen-activated protein kinase 14 Neuropsychopharmacology (to MK). The funding agencies had no further role in study design or in the collection, analysis and NOS1AP Nitric oxide synthase 1 adaptor protein RASD1 Ras related dexamethasone induced 1 interpretation of data. CPE Carboxypeptidase E SYN1 Synapsin I REFERENCES DLG1 Discs large MAGUK scaffold protein 1 SCRIB Scribbled planar cell polarity protein 1. Freudenberg F et al., 2015. Neuronal nitric oxide synthase (NOS1) and its adaptor, NOS1AP, as a genetic risk factors for DLG3 MAP2K3 Discs large MAGUK scaffold protein 3 Mitogen-activated protein kinase kinase 3 psychiatric disorders. Genes Brain Behav. 14(1):46-63. DLG4 GUCY1B2 Discs large MAGUK scaffold protein 4 Guanylate cyclase 1 soluble subunit beta 2 2. Eastwood SL. 2005. Does the CAPON gene confer susceptibility to schizophrenia? PLoS Med. 2(10):e348. GRIA1 Glutamate ionotropic receptor AMPA type subunit 1 GUCY1A1 Guanylate cyclase 1 soluble subunit alpha 1 3. Candemir E et al., 2016. Interaction of NOS1AP with the NOS-I PDZ domain: Implications for schizophrenia-related GRIA2 Glutamate ionotropic receptor AMPA type subunit 2 GUCY1A2 Guanylate cyclase 1 soluble subunit alpha 2 alterations in dendritic morphology. Eur Neuropsychopharmacol. 26(4):741-55. GRIN2A Glutamate ionotropic receptor NMDA type subunit 2A GUCY1B1 Guanylate cyclase 1 soluble subunit beta 1 4. Greenwood TA et al., 2016. Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. Schizophr. Res. 170(1): 30-40. GRIN2B Glutamate ionotropic receptor NMDA type subunit 2B 5. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000979.v1.p1 .
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