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Poster #112 GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) SERUM LEVELS IN SCHIZOPHRENIC WOMEN DURING 8-WEEKS OF TREATMENT
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Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
Poster #111 EPISTATIC INTERACTION OF COMT AND DTNBP1 MODULATES WORKING MEMORY PERFORMANCE IN MICE AND RELATED PREFRONTAL PHYSIOLOGY IN HUMANS Francesco Papaleo 1,2 , Madeline Burdick 2 , Joseph Callicott 2 , Daniel Weinberger 2 1 Istituto Italiano di Tecnologia, Genova, Italy; 2 National Institute of Mental Health, Bethesda, MD, USA Background: The etiology of schizophrenia is complex and largely unknown, with both genetic and environmental contributing factors. Genetic association studies have indicated several potential schizophreniasusceptibility genes such as Dysbindin, COMT, DISC1, KCNH2, Neuregulin1 etc. Schizophrenia is most likely related to the combination of malfunction of multiple genes, rather than mutation of only a single gene. Based on the dopamine/D2 trafficking effects and the well characterized inverted U-shaped dopamine response relationship in prefrontal cortex (PFC), we predicted that decreased dysbindin expression and increased synaptic dopamine would translate into abnormal D2 signaling which would be disadvantageous for PFC-dependent cognitive functions. Methods: We investigated the interacting effects between COMT and dysbindin in both mouse and human paradigms. We produced single (COMT or dysbindin) and COMT*dysbindin double knockout mice and tested them in the working memory and PFC-dependent discrete paired-trial variabledelay T-maze task. For the human fMRI experiment, normal subjects (N=115) performed the N-back working memory task. The effect of a DTNBP1 haplotype associated with decreased expression of dysbindin in human prefrontal cortex (Bray et al 2005) was tested on the background of COMT Val/Met genotypes. Results: Compared with wild-type animals, each single knockout mouse required fewer days to achieve criteria, but the combined COMT*dysbindin gene knockouts, either combined heterozygotes or combined homozygotes, showed a dramatic delay in learning the task. In the human fMRI data, COMT Met alleles associated with relatively greater synaptic dopamine and more physiologically efficient in general, were significantly less efficient on the background of the low-DTNBP1 Bray risk associated haplotype. On the background of non-risk Bray haplotypes, the COMT Met allele was the most efficient. Discussion: These results confirm at the level of mouse working memory and human working memory physiology epistatic interactions of DTNBP1 and COMT that are consistent with predictions from basic model systems about the nonlinear relationship between cortical dopamine signaling and cortical function. These results also have implications for understanding variation in genetic association of individual genes across different populations, because genetic background in relevant pathways is not generally considered.
Poster #112 GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) SERUM LEVELS IN SCHIZOPHRENIC WOMEN DURING 8-WEEKS OF TREATMENT Aleksandra Rajewska-Rager 1,2 , Maria Skibinska 2 , Pawel Kapelski 1,2 , Anna Leszczynska-Rodziewicz 1,2, Joanna Pawlak 2 , Hauser Joanna 1,2 1 University of Medical Sciences,Department of Adult Psychiatry, Poznan, Poland; 2 University of Medical Sciences, Laboratory of Psychiatric Genetics, Poznan, Poland Background: Findings from pharmacogenetic studies indicates that GDNF is strong candidate to be a biological marker of psychiatric diseases, but there are still many inconsistent results. Glial-Derived Neurotrophic Factor (GDNF) is a neurotrophic factor from the transforming growth factor βfamily, which plays a role in the development and function of hippocampus and other brain regions. GDNF exerts neurotrophic effect on the development and maintenance of glial cells, but also on dopaminergic, serotonergic, noradrenergic and GABA-ergic systems. It protects neural and glial cells against oxidative stress. Based on dopamine theory and the neurodevelopmental hypothesis of schizophrenia we suspect that alterations of GDNF functions may be involved in the pathogenesis of schizophrenia. Methods: 25 females diagnosed with schizophrenia (mean age 32.4, SD 11.2) and 25 matched controls (mean age 31.8, SD 10.5) were enrolled in
the study. Patients were recruited during acute episode, on the admission to the psychiatry ward in the Department of Psychiatry, Poznan Universityof Medical Sciences. Diagnosis was made according to American DSMIV and European ICD10 criteria using Structured Clinical Interview for DSM-IV (SCID). Psychopathology and severity of positive and negative symptoms of schizophrenia was assessed using the Positive and Negative Syndrom Scale (PANSS). Diagnosis was confirmed by two experienced psychiatrists. The study was approved by the Local Ethic Committee. All persons taking part in the study gave written informed consent for participation. Blood was collected and serum separated and stored at -70 on admission and after 8 weeks of treatment. ELISA analyses were performed using DuoSet ELISA Development Kits (R&D Systems). Normality of the GDNF serum level was tested using Kolmogorov-Smirnov test. Mann-Whitney U-test was applied to compare GDNF serum levels between patients and controls. Wilcoxon signed-rank pair test was used to investigate serum neurotrophins changes during 8-weeks treatment. Results: Serum levels of GDNF were not normally distributed. There were no significant differences between schizophrenia group and control group comparing GDNF serum levels at the beginning of the study (p=0,41) and after 8 weeks of treatment (p=0,83). No significant differences in serum GDNF level during treatment have been found (p=0,91). We didn’t found correlation with PANSS total sores and PANSS P, PANNS N PANSS G subscales. Discussion: In our group serum GDNF levels at the beginning of the study and after 8 weeks of treatment was without significant differences. Further studies on larger group in Polish population are necessary. This work was supported by Polish Ministry of Science and Higher Education grant no. MNiSW NN402243635.
Poster #113 BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), NEUROTROPHIN 3 (NTF3), NEUROTROPHIN 4 (NTF4) AND GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) SERUM LEVELS IN SCHIZOPHRENIA Anna Leszczynska-Rodziewicz, Maria Skibinska, Paweł Kapelski, Aleksandra Rajewska-Rager, Joanna Pawlak, Joanna Hauser University of Medical Sciences, Poznan, Poland Background: The neurodevelopmental hypothesis of schizophrenia postulates neurogenesis and explains these changes as the result of disturbancess of processes involving the trophic factors like BDNF, NT3, NT4 and GDNF. These are structurally diverse group of endogenous proteins which regulate the survival and multiple other cellular functions of neurons. Methods: 38 females diagnosed with schizophrenia (mean age 31.5, SD 10.3) and 38 matched controls (mean age 37.6, SD 12.9) were enrolled in the study. Patients were recruited during acute episode, on the admission to the psychiatry ward in the Department of Psychiatry, Poznan Univeristy of Medical Sciences. Diagnosis was made according to DSMIV and ICD10 criteria using Structured Clinical Interview for DSM-IV (SCID). Psychopathology was assessed using the Positive and Negative Syndrom Scale (PANSS). Diagnosis was confirmed by two experienced psychiatrists. The study was approved by the Local Ethic Committee. All persons taking part in the study gave written informed consent for participation. 10 ml of venous blood was withdrawn between 7.30 and 9.30 a.m. after overnight fast into anticoagulant-free tubes. After 1h incubation serum was separated by centrifugation, aliquoted and stored at -70 until analysis. ELISA analyses were performed using DuoSet ELISA Development Kits (R&D Systems). Normality of the BDNF, NT3, NT4 and GDNF serum level was tested using Kolmogorov-Smirnov test. Mann-Whitney U-test was applied to compare neurotrophic factor serum levels between patients and controls. Correlation between neurotrophic factors serum levels and PANSS scores was performed using Spearman’s correlation rank test. Results: Serum levels of BDNF, NT3, NT4 and GDNF were not normally distributed. Statistical trend (p=0.06) was observed comparing BDNF serum level between schizophrenic women and healthy controls, with higher BDNF level in patients. Strong positive correlation was observed between NT3 and NT4 serum level (p<0.1×10-11 ) and between GDNF and NT3 (p<0.5) as well as NT4 (p<0.01). Negative correlation (p<0.05) between GDNF serum level and PANSS N subscale was noticed. Discussion: Studies performed on serum/plasma levels of BDNF, NT3, NT4,GDNF in schizophrenia are inconsistent. The elvels may be regulated
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
Poster #111 EPISTATIC INTERACTION OF COMT AND DTNBP1 MODULATES WORKING MEMORY PERFORMANCE IN MICE AND RELATED PREFRONTAL PHYSIOLOGY IN HUMANS Francesco Papaleo 1,2 , Madeline Burdick 2 , Joseph Callicott 2 , Daniel Weinberger 2 1 Istituto Italiano di Tecnologia, Genova, Italy; 2 National Institute of Mental Health, Bethesda, MD, USA Background: The etiology of schizophrenia is complex and largely unknown, with both genetic and environmental contributing factors. Genetic association studies have indicated several potential schizophreniasusceptibility genes such as Dysbindin, COMT, DISC1, KCNH2, Neuregulin1 etc. Schizophrenia is most likely related to the combination of malfunction of multiple genes, rather than mutation of only a single gene. Based on the dopamine/D2 trafficking effects and the well characterized inverted U-shaped dopamine response relationship in prefrontal cortex (PFC), we predicted that decreased dysbindin expression and increased synaptic dopamine would translate into abnormal D2 signaling which would be disadvantageous for PFC-dependent cognitive functions. Methods: We investigated the interacting effects between COMT and dysbindin in both mouse and human paradigms. We produced single (COMT or dysbindin) and COMT*dysbindin double knockout mice and tested them in the working memory and PFC-dependent discrete paired-trial variabledelay T-maze task. For the human fMRI experiment, normal subjects (N=115) performed the N-back working memory task. The effect of a DTNBP1 haplotype associated with decreased expression of dysbindin in human prefrontal cortex (Bray et al 2005) was tested on the background of COMT Val/Met genotypes. Results: Compared with wild-type animals, each single knockout mouse required fewer days to achieve criteria, but the combined COMT*dysbindin gene knockouts, either combined heterozygotes or combined homozygotes, showed a dramatic delay in learning the task. In the human fMRI data, COMT Met alleles associated with relatively greater synaptic dopamine and more physiologically efficient in general, were significantly less efficient on the background of the low-DTNBP1 Bray risk associated haplotype. On the background of non-risk Bray haplotypes, the COMT Met allele was the most efficient. Discussion: These results confirm at the level of mouse working memory and human working memory physiology epistatic interactions of DTNBP1 and COMT that are consistent with predictions from basic model systems about the nonlinear relationship between cortical dopamine signaling and cortical function. These results also have implications for understanding variation in genetic association of individual genes across different populations, because genetic background in relevant pathways is not generally considered.
Poster #112 GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) SERUM LEVELS IN SCHIZOPHRENIC WOMEN DURING 8-WEEKS OF TREATMENT Aleksandra Rajewska-Rager 1,2 , Maria Skibinska 2 , Pawel Kapelski 1,2 , Anna Leszczynska-Rodziewicz 1,2, Joanna Pawlak 2 , Hauser Joanna 1,2 1 University of Medical Sciences,Department of Adult Psychiatry, Poznan, Poland; 2 University of Medical Sciences, Laboratory of Psychiatric Genetics, Poznan, Poland Background: Findings from pharmacogenetic studies indicates that GDNF is strong candidate to be a biological marker of psychiatric diseases, but there are still many inconsistent results. Glial-Derived Neurotrophic Factor (GDNF) is a neurotrophic factor from the transforming growth factor βfamily, which plays a role in the development and function of hippocampus and other brain regions. GDNF exerts neurotrophic effect on the development and maintenance of glial cells, but also on dopaminergic, serotonergic, noradrenergic and GABA-ergic systems. It protects neural and glial cells against oxidative stress. Based on dopamine theory and the neurodevelopmental hypothesis of schizophrenia we suspect that alterations of GDNF functions may be involved in the pathogenesis of schizophrenia. Methods: 25 females diagnosed with schizophrenia (mean age 32.4, SD 11.2) and 25 matched controls (mean age 31.8, SD 10.5) were enrolled in
the study. Patients were recruited during acute episode, on the admission to the psychiatry ward in the Department of Psychiatry, Poznan Universityof Medical Sciences. Diagnosis was made according to American DSMIV and European ICD10 criteria using Structured Clinical Interview for DSM-IV (SCID). Psychopathology and severity of positive and negative symptoms of schizophrenia was assessed using the Positive and Negative Syndrom Scale (PANSS). Diagnosis was confirmed by two experienced psychiatrists. The study was approved by the Local Ethic Committee. All persons taking part in the study gave written informed consent for participation. Blood was collected and serum separated and stored at -70 on admission and after 8 weeks of treatment. ELISA analyses were performed using DuoSet ELISA Development Kits (R&D Systems). Normality of the GDNF serum level was tested using Kolmogorov-Smirnov test. Mann-Whitney U-test was applied to compare GDNF serum levels between patients and controls. Wilcoxon signed-rank pair test was used to investigate serum neurotrophins changes during 8-weeks treatment. Results: Serum levels of GDNF were not normally distributed. There were no significant differences between schizophrenia group and control group comparing GDNF serum levels at the beginning of the study (p=0,41) and after 8 weeks of treatment (p=0,83). No significant differences in serum GDNF level during treatment have been found (p=0,91). We didn’t found correlation with PANSS total sores and PANSS P, PANNS N PANSS G subscales. Discussion: In our group serum GDNF levels at the beginning of the study and after 8 weeks of treatment was without significant differences. Further studies on larger group in Polish population are necessary. This work was supported by Polish Ministry of Science and Higher Education grant no. MNiSW NN402243635.
Poster #113 BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), NEUROTROPHIN 3 (NTF3), NEUROTROPHIN 4 (NTF4) AND GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) SERUM LEVELS IN SCHIZOPHRENIA Anna Leszczynska-Rodziewicz, Maria Skibinska, Paweł Kapelski, Aleksandra Rajewska-Rager, Joanna Pawlak, Joanna Hauser University of Medical Sciences, Poznan, Poland Background: The neurodevelopmental hypothesis of schizophrenia postulates neurogenesis and explains these changes as the result of disturbancess of processes involving the trophic factors like BDNF, NT3, NT4 and GDNF. These are structurally diverse group of endogenous proteins which regulate the survival and multiple other cellular functions of neurons. Methods: 38 females diagnosed with schizophrenia (mean age 31.5, SD 10.3) and 38 matched controls (mean age 37.6, SD 12.9) were enrolled in the study. Patients were recruited during acute episode, on the admission to the psychiatry ward in the Department of Psychiatry, Poznan Univeristy of Medical Sciences. Diagnosis was made according to DSMIV and ICD10 criteria using Structured Clinical Interview for DSM-IV (SCID). Psychopathology was assessed using the Positive and Negative Syndrom Scale (PANSS). Diagnosis was confirmed by two experienced psychiatrists. The study was approved by the Local Ethic Committee. All persons taking part in the study gave written informed consent for participation. 10 ml of venous blood was withdrawn between 7.30 and 9.30 a.m. after overnight fast into anticoagulant-free tubes. After 1h incubation serum was separated by centrifugation, aliquoted and stored at -70 until analysis. ELISA analyses were performed using DuoSet ELISA Development Kits (R&D Systems). Normality of the BDNF, NT3, NT4 and GDNF serum level was tested using Kolmogorov-Smirnov test. Mann-Whitney U-test was applied to compare neurotrophic factor serum levels between patients and controls. Correlation between neurotrophic factors serum levels and PANSS scores was performed using Spearman’s correlation rank test. Results: Serum levels of BDNF, NT3, NT4 and GDNF were not normally distributed. Statistical trend (p=0.06) was observed comparing BDNF serum level between schizophrenic women and healthy controls, with higher BDNF level in patients. Strong positive correlation was observed between NT3 and NT4 serum level (p<0.1×10-11 ) and between GDNF and NT3 (p<0.5) as well as NT4 (p<0.01). Negative correlation (p<0.05) between GDNF serum level and PANSS N subscale was noticed. Discussion: Studies performed on serum/plasma levels of BDNF, NT3, NT4,GDNF in schizophrenia are inconsistent. The elvels may be regulated