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Variants of the RELA gene are associated with schizophrenia and prepulse inhibition
Abstracts / Neuroscience Research 71S (2011) e108–e415
brain surface. However, there is no study where the ERP on brain surface is directly compared with LFP simultaneously recorded from hippocampus. In the present study, we performed simultaneous recordings of auditory evoked potentials (AEPs) to 200 pairs of clicks (80 dB SPL, duration = 20 ms, inter-click-interval = 0.5 s, inter-pair-interval = 4 s) from brain surface and hippocampal CA3 area in freely moving rats. Then, we compared the waveforms calculated by averaging the AEP responses. The brain surface AEP showed clear gating response: while the first click evoked a V-shaped response lasting from 28 ms to 66 ms after the click with the negative peak at 38 ms after the click (1.57 microvolts in amplitude measured from the baseline), the second click did not evoked clear response in the same range. On the other hand, hippocampal AEP showed only weak gating response: the second click evoked a clear V-shaped response lasting from 16 ms to 46 ms after the click with the negative peak at 30 ms after the click in the same way as the first click. The amplitude of the response to the first click was 9.25 microvolts and that to the second click was 7.61 microvolts. The test (second click) to conditioning (first click) ratio of the amplitudes was 0.82. The gap suggests that the gating response of the brain surface AEP is not always analogue of the neuronal activities in hippocampus. doi:10.1016/j.neures.2011.07.1730
P4-r10 Akt1 deficiency causes alterations in hippocampal neuromorphology and hippocampus-dependent cognitive function Yi-Wen Chen 1 , Wan-Ting Chang 1 , Wen-Sung Lai 1,2 1
Department of Psychology, National Taiwan University, Taipei, Taiwan 2 Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan Accumulating evidence suggests that Akt1 (PKB alpha) not only contributes to schizophrenia-related phenotypes but also involves in the neurite outgrowth (e.g., elongation, branching, and caliber). To establish a closer link between Akt1 deficiency and hippocampal functions, mice with Akt1 deficiency and hippocampal pyramidal neurons partially labeled with GFP were used to investigate the roles of AKT1 in hippocampal neuromorphology and cognitive functions. Three hippocampus-dependent behavioral tasks (including Y-maze, passive avoidance, and Morris water maze) were first conducted in Akt1 knockout mice and their wild-type littermates and neuromorphological examination of hippocampal pyramidal neurons were performed afterward. Our preliminary data revealed that Akt1 knockout mice demonstrated impairments in recall of spatial memory on the Y-maze and they also displayed differential impairments in the water maze during the spatial learning, spatial memory, and reversal of spatial learning compared with their wild-type controls. Neuromorphological analysis further indicated that Akt1 knockout mice had several neuromorphological alterations in hippocampal pyramidal neurons compared with their wild-type controls. In the apical dendrites, there were (1) a 32% reduction in the number of branches, and (2) a 29% decrease in the number of tips. In the basal dendrites, these alterations included (1) a slight (20%) but significant increase in soma size, (2) a 28% reduction in the number of branches, (3) a 22% decrease in the number of tips, and (4) a 18% decline in the total length. These decreases in complexity were also confirmed by Sholl analysis. Taken together, our preliminary data implicated the involvement of AKT1 in hippocampus-dependent cognitive functions and hippocampal neuromorphology in vivo. Research fund: This research was supported by grants 99-2410-H-002-088MY3 and 99-2218-E-007-002- from the National Science Council, Taiwan, and the Excellent Research Projects of NTU. doi:10.1016/j.neures.2011.07.1731
P4-r11 Association between EGR3 gene polymorphism and prefrontal hemodynamic response during cognitive task in patients with schizophrenia Yukika Nishimura 1 , Ryu Takizawa 1 , Shinsuke Koike 1 , Mamoru Tochigi 1 , Tsukasa Sasaki 2,3 , Takeo Yoshikawa 4 , Kiyoto Kasai 1 1 Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan 2 Health Service Center, University of Tokyo 3 Office for Mental Health Support and Graduate School of Education, University of Tokyo 4 Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute
Early Growth Response 3 (EGR3) gene is located on the chromosome 8p21.3, and previous report suggests a potential susceptibility gene to schizophrenia in Japanese population (Yamada et al., 2007). The aim of the present study is to examine the association between the EGR3 gene polymorphism and prefrontal hemodynamic response during cognitive task in patients with
e395
schizophrenia. The subjects were 73 chronic patients with schizophrenia and 73 healthy controls, who gave written informed consent to participate. We measured changes in the prefrontal oxygenated hemoglobin concentration (oxyHb) during the letter version of a verbal fluency task using multi-channel near-infrared spectroscopy (NIRS) imaging. We also examined the relationship between the prefrontal oxyHb changes during the verbal fluency task and psychotic symptoms assessed by the PANSS in patients with schizophrenia. The statistical comparisons were performed between two EGR3 genotype subgroups (rs35201266, M228, GG/GA) because the sample size of the AA genotype was too small to provide sufficient statistical power. The two genotype-subgroups were age-, gender-, and task-performancematched in each group. Contrary to our expectation, the oxyHb changes in the prefrontal cortex of the GG genotype group show a smaller tendency than that of the GA genotype group in patients with schizophrenia, while such differences were not shown in healthy controls. Furthermore, only in the GG genotype group with schizophrenia, the total score of the PANSS was positively correlated with the oxyHb changes in the prefrontal cortex. These results suggest the possibility that the EGR3 might be involved in the clinical condition of schizophrenia intricately. Research fund: A part of this study was the result of ‘Development of biomarker candidates for social behavior’ carried out under the Strategic Research Program for Brain Sciences by the MEXT. doi:10.1016/j.neures.2011.07.1732
P4-r12 Variants of the RELA gene are associated with schizophrenia and prepulse inhibition Ryota Hashimoto 1,2,4,7 , Kazutaka Ohi 2,4 , Yuka Yasuda 2,4 , Yamamori 2,3,4 , Hidetoshi Motoyuki Fukumoto 2,4 , Hidenaga Takahashi 2 , Masao Iwase 2 , Tomo Okochi 4,5 , Hiroaki Kazui 2 , Osamu Saitoh 6 , Masahiko Tatsumi 8 , Nakao Iwata 4,5 , Norio Ozaki 4,9 , Kunitoshi Kamijima 10 , Hiroshi Kunugi 7 , Masatoshi Takeda 1,2 1 Mol. Res. Cent. for Child. Mental. Dev., United Grad. Sch. of Child. Dev., Osaka Univ., Suita, Japan 2 Dept. of Psychiat., Osaka Univ. Grad. Sch. of Med., Suita, Japan 3 Dept. of Mol. Neuropsychiat., Osaka Univ. Grad. Sch. of Med., Suita, Japan 4 CREST of JST, Saitama, Japan 5 Dept. of Psychiat., Fujita Health Univ. Sch. of Med., Aichi, Japan 6 Natl. Cent. Hosp., NCNP, Kodaira, Japan 7 Dept. of Mental Dis. Res., Natl. Inst. of Neuroscie., NCNP Kodaira, Japan 8 Yokohama Shinryo Clinic, Yokohama, Japan 9 Dept. of Psychiat., Nagoya Univ. Grad. Sch. of Med., Nagoya, Japan 10 Dept. of Psychiat., Showa Univ. Sch. of Med., Tokyo, Japan
The pathogenesis of schizophrenia is thought to involve aberrant immune and inflammatory responses. Nuclear factor kappa B (NF-B) plays important roles in the immune and inflammatory responses. The v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) gene encodes the major component of the NF-B complex. We genotyped four single nucleotide polymorphisms (SNPs) in the RELA gene and performed a gene-based association analysis using 1224 patients with schizophrenia and 1663 controls. We found significant associations of three SNPs with schizophrenia and stronger evidence for association in a multi-marker haplotype analysis. The association between this gene and schizophrenia was evident in male subjects but not in female subjects, when separately analyzed by gender. In silico genotype-gene expression analysis using web database revealed that these three schizophrenia-associated SNPs might be related to RELA mRNA expression in immortalized B-lymphocytes. In silico analysis also suggested the putative promoter SNP, rs11820062, might disrupts the consensus transcription factor binding sequence of the androgen receptor. We provided further evidence that at risk genotypes of three SNPs were associated with deficits in prepulse inhibition (PPI), however, there was no effect of the one non-risk SNP on PPI in 53 patients with schizophrenia. These findings suggest that variants of the RELA gene are associated with risk for schizophrenia and PPI deficits in a Japanese population. doi:10.1016/j.neures.2011.07.1733
brain surface. However, there is no study where the ERP on brain surface is directly compared with LFP simultaneously recorded from hippocampus. In the present study, we performed simultaneous recordings of auditory evoked potentials (AEPs) to 200 pairs of clicks (80 dB SPL, duration = 20 ms, inter-click-interval = 0.5 s, inter-pair-interval = 4 s) from brain surface and hippocampal CA3 area in freely moving rats. Then, we compared the waveforms calculated by averaging the AEP responses. The brain surface AEP showed clear gating response: while the first click evoked a V-shaped response lasting from 28 ms to 66 ms after the click with the negative peak at 38 ms after the click (1.57 microvolts in amplitude measured from the baseline), the second click did not evoked clear response in the same range. On the other hand, hippocampal AEP showed only weak gating response: the second click evoked a clear V-shaped response lasting from 16 ms to 46 ms after the click with the negative peak at 30 ms after the click in the same way as the first click. The amplitude of the response to the first click was 9.25 microvolts and that to the second click was 7.61 microvolts. The test (second click) to conditioning (first click) ratio of the amplitudes was 0.82. The gap suggests that the gating response of the brain surface AEP is not always analogue of the neuronal activities in hippocampus. doi:10.1016/j.neures.2011.07.1730
P4-r10 Akt1 deficiency causes alterations in hippocampal neuromorphology and hippocampus-dependent cognitive function Yi-Wen Chen 1 , Wan-Ting Chang 1 , Wen-Sung Lai 1,2 1
Department of Psychology, National Taiwan University, Taipei, Taiwan 2 Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan Accumulating evidence suggests that Akt1 (PKB alpha) not only contributes to schizophrenia-related phenotypes but also involves in the neurite outgrowth (e.g., elongation, branching, and caliber). To establish a closer link between Akt1 deficiency and hippocampal functions, mice with Akt1 deficiency and hippocampal pyramidal neurons partially labeled with GFP were used to investigate the roles of AKT1 in hippocampal neuromorphology and cognitive functions. Three hippocampus-dependent behavioral tasks (including Y-maze, passive avoidance, and Morris water maze) were first conducted in Akt1 knockout mice and their wild-type littermates and neuromorphological examination of hippocampal pyramidal neurons were performed afterward. Our preliminary data revealed that Akt1 knockout mice demonstrated impairments in recall of spatial memory on the Y-maze and they also displayed differential impairments in the water maze during the spatial learning, spatial memory, and reversal of spatial learning compared with their wild-type controls. Neuromorphological analysis further indicated that Akt1 knockout mice had several neuromorphological alterations in hippocampal pyramidal neurons compared with their wild-type controls. In the apical dendrites, there were (1) a 32% reduction in the number of branches, and (2) a 29% decrease in the number of tips. In the basal dendrites, these alterations included (1) a slight (20%) but significant increase in soma size, (2) a 28% reduction in the number of branches, (3) a 22% decrease in the number of tips, and (4) a 18% decline in the total length. These decreases in complexity were also confirmed by Sholl analysis. Taken together, our preliminary data implicated the involvement of AKT1 in hippocampus-dependent cognitive functions and hippocampal neuromorphology in vivo. Research fund: This research was supported by grants 99-2410-H-002-088MY3 and 99-2218-E-007-002- from the National Science Council, Taiwan, and the Excellent Research Projects of NTU. doi:10.1016/j.neures.2011.07.1731
P4-r11 Association between EGR3 gene polymorphism and prefrontal hemodynamic response during cognitive task in patients with schizophrenia Yukika Nishimura 1 , Ryu Takizawa 1 , Shinsuke Koike 1 , Mamoru Tochigi 1 , Tsukasa Sasaki 2,3 , Takeo Yoshikawa 4 , Kiyoto Kasai 1 1 Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan 2 Health Service Center, University of Tokyo 3 Office for Mental Health Support and Graduate School of Education, University of Tokyo 4 Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute
Early Growth Response 3 (EGR3) gene is located on the chromosome 8p21.3, and previous report suggests a potential susceptibility gene to schizophrenia in Japanese population (Yamada et al., 2007). The aim of the present study is to examine the association between the EGR3 gene polymorphism and prefrontal hemodynamic response during cognitive task in patients with
e395
schizophrenia. The subjects were 73 chronic patients with schizophrenia and 73 healthy controls, who gave written informed consent to participate. We measured changes in the prefrontal oxygenated hemoglobin concentration (oxyHb) during the letter version of a verbal fluency task using multi-channel near-infrared spectroscopy (NIRS) imaging. We also examined the relationship between the prefrontal oxyHb changes during the verbal fluency task and psychotic symptoms assessed by the PANSS in patients with schizophrenia. The statistical comparisons were performed between two EGR3 genotype subgroups (rs35201266, M228, GG/GA) because the sample size of the AA genotype was too small to provide sufficient statistical power. The two genotype-subgroups were age-, gender-, and task-performancematched in each group. Contrary to our expectation, the oxyHb changes in the prefrontal cortex of the GG genotype group show a smaller tendency than that of the GA genotype group in patients with schizophrenia, while such differences were not shown in healthy controls. Furthermore, only in the GG genotype group with schizophrenia, the total score of the PANSS was positively correlated with the oxyHb changes in the prefrontal cortex. These results suggest the possibility that the EGR3 might be involved in the clinical condition of schizophrenia intricately. Research fund: A part of this study was the result of ‘Development of biomarker candidates for social behavior’ carried out under the Strategic Research Program for Brain Sciences by the MEXT. doi:10.1016/j.neures.2011.07.1732
P4-r12 Variants of the RELA gene are associated with schizophrenia and prepulse inhibition Ryota Hashimoto 1,2,4,7 , Kazutaka Ohi 2,4 , Yuka Yasuda 2,4 , Yamamori 2,3,4 , Hidetoshi Motoyuki Fukumoto 2,4 , Hidenaga Takahashi 2 , Masao Iwase 2 , Tomo Okochi 4,5 , Hiroaki Kazui 2 , Osamu Saitoh 6 , Masahiko Tatsumi 8 , Nakao Iwata 4,5 , Norio Ozaki 4,9 , Kunitoshi Kamijima 10 , Hiroshi Kunugi 7 , Masatoshi Takeda 1,2 1 Mol. Res. Cent. for Child. Mental. Dev., United Grad. Sch. of Child. Dev., Osaka Univ., Suita, Japan 2 Dept. of Psychiat., Osaka Univ. Grad. Sch. of Med., Suita, Japan 3 Dept. of Mol. Neuropsychiat., Osaka Univ. Grad. Sch. of Med., Suita, Japan 4 CREST of JST, Saitama, Japan 5 Dept. of Psychiat., Fujita Health Univ. Sch. of Med., Aichi, Japan 6 Natl. Cent. Hosp., NCNP, Kodaira, Japan 7 Dept. of Mental Dis. Res., Natl. Inst. of Neuroscie., NCNP Kodaira, Japan 8 Yokohama Shinryo Clinic, Yokohama, Japan 9 Dept. of Psychiat., Nagoya Univ. Grad. Sch. of Med., Nagoya, Japan 10 Dept. of Psychiat., Showa Univ. Sch. of Med., Tokyo, Japan
The pathogenesis of schizophrenia is thought to involve aberrant immune and inflammatory responses. Nuclear factor kappa B (NF-B) plays important roles in the immune and inflammatory responses. The v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) gene encodes the major component of the NF-B complex. We genotyped four single nucleotide polymorphisms (SNPs) in the RELA gene and performed a gene-based association analysis using 1224 patients with schizophrenia and 1663 controls. We found significant associations of three SNPs with schizophrenia and stronger evidence for association in a multi-marker haplotype analysis. The association between this gene and schizophrenia was evident in male subjects but not in female subjects, when separately analyzed by gender. In silico genotype-gene expression analysis using web database revealed that these three schizophrenia-associated SNPs might be related to RELA mRNA expression in immortalized B-lymphocytes. In silico analysis also suggested the putative promoter SNP, rs11820062, might disrupts the consensus transcription factor binding sequence of the androgen receptor. We provided further evidence that at risk genotypes of three SNPs were associated with deficits in prepulse inhibition (PPI), however, there was no effect of the one non-risk SNP on PPI in 53 patients with schizophrenia. These findings suggest that variants of the RELA gene are associated with risk for schizophrenia and PPI deficits in a Japanese population. doi:10.1016/j.neures.2011.07.1733