PM376. Mountain-cultivated ginseng attenuates phencyclidine (PCP)-induced schizophrenia-like psychosis in mice

s | 37 Abstract Large-scale genome-wide association studies have identified susceptibility loci for schizophrenia in the gene encoding neurogranin (NRGN). Neurogranin is a neuron-specific calmodulin binding protein abundantly expressed in brain regions implicated in schizophrenia pathophysiology, such as the hippocampus and prefrontal cortex. Nrgn knockout (KO) mice were previously shown to exhibit aberrant behavioral phenotypes involving deficits in cognitive functions and abnormal emotional behaviors. In this study, we examined additional behavioral and molecular traits relevant to schizophrenia in Nrgn KO mice. The mutant mice exhibited a series of behavioral abnormalities that resemble those of schizophrenics, including hyper-locomotor activity and impairments in working memory, social behavior and sensorimotor gating. In the DG, mRNA expressions of immature and mature granule cell (GC) markers were not significantly changed in almost all young mutant mice (<10 weeks old). On the other hand, older animals (>20 weeks old) showed increased expression of immature GC markers and decreased expression of mature GC markers. Bioinformatics analyses of transcriptome data also revealed that the gene expression patterns of the DG of older mutants are significantly similar to those of normal young mice. These results indicate that adult but not juvenile Nrgn KO mice show immature DG phenotype, which has been proposed as a novel endophenotype of schizophrenia, and that both genetic and undetermined (e.g., stress and aging) factors might act together to reverse matured GCs to a pseudo-immature status. Nrgn KO mice might be a novel animal model recapitulating the fact that typical onset of schizophrenia occurs during late adolescence or early adulthood. The late onset of the immature phenotypes would provide unique opportunities for studying molecular mechanisms of the disorder.Large-scale genome-wide association studies have identified susceptibility loci for schizophrenia in the gene encoding neurogranin (NRGN). Neurogranin is a neuron-specific calmodulin binding protein abundantly expressed in brain regions implicated in schizophrenia pathophysiology, such as the hippocampus and prefrontal cortex. Nrgn knockout (KO) mice were previously shown to exhibit aberrant behavioral phenotypes involving deficits in cognitive functions and abnormal emotional behaviors. In this study, we examined additional behavioral and molecular traits relevant to schizophrenia in Nrgn KO mice. The mutant mice exhibited a series of behavioral abnormalities that resemble those of schizophrenics, including hyper-locomotor activity and impairments in working memory, social behavior and sensorimotor gating. In the DG, mRNA expressions of immature and mature granule cell (GC) markers were not significantly changed in almost all young mutant mice (<10 weeks old). On the other hand, older animals (>20 weeks old) showed increased expression of immature GC markers and decreased expression of mature GC markers. Bioinformatics analyses of transcriptome data also revealed that the gene expression patterns of the DG of older mutants are significantly similar to those of normal young mice. These results indicate that adult but not juvenile Nrgn KO mice show immature DG phenotype, which has been proposed as a novel endophenotype of schizophrenia, and that both genetic and undetermined (e.g., stress and aging) factors might act together to reverse matured GCs to a pseudo-immature status. Nrgn KO mice might be a novel animal model recapitulating the fact that typical onset of schizophrenia occurs during late adolescence or early adulthood. The late onset of the immature phenotypes would provide unique opportunities for studying molecular mechanisms of the disorder. PM375 Electroconvulsive shock ameliorated the schizophrenia-like behavior and attenuated the glial activation in the hippocampus of Gunn Rat Erlyn Limoa Ilhamuddin Abdul Aziz, Tomoko Araki, Ryosuke Arauchi, Motohide Furuya, Sadayuki Hashioka, Maiko Hayashida, Jun Horiguchi, Kristian Liaury, Tsuyoshi Miyaoka, Andi Jayalangkara Tanra, Keiko Tsuchie, Rei Wake Shimane University, Faculty of Medicine, Japan ABSTRACT Background: Although electroconvulsive therapy (ECT) is regarded as one of the efficient treatments for intractable psychiatric disorders, the mechanism of therapeutic action remains unclear. Recently, many studies indicate that ECT affects the immune system, including the immune-related cells, such as microglia, astrocytes, and lymphocytes. Moreover, microglial and astrocytic activation has been implicated in postmortem brains of schizophrenia patients. We previously demonstrated that Gunn rats showed schizophrenia-like behavior and microglial activation in their brains. In this study we examined the effects of electroconvulsive shock (ECS), an animal counterpart of ECT, on schizophrenia-like behavior, microgliosis and astrogliosis in the hippocampus of Gunn rats. Methods: The rats were divided into 4 groups, i.e., Wistar sham, Wistar ECS, Gunn sham and Gunn ECS. ECS groups received ECS once daily for 6 consecutive days. Subsequently, prepulse inhibition test (PPI) was performed on all animals. After PPI, immunohistochemistry analysis was carried out to determine microglial activation and astrocytic activation, using anti-CD11b and antiGFAP antibody, respectively. Results: We found PPI deficit in Gunn rats compared to Wistar rats, and it was significantly improved by ECS. In immunohistochemistry analysis revealed that there is significant higher expression of CD11b and GFAP in Gunn rats compared to Wistar rats. ECS attenuated the expression of both CD11b and GFAP in Gunn rats. The effect of ECS on the number of microglia in the hippocampus will be shown in the poster presentation. Conclusion: Our findings indicate that ECS ameliorates schizophrenia-like behavior in Gunn rats and attenuates both microglial activation and astrocytic activation in the hippocampus of Gunn rats. Accordingly, therapeutic effects of ECT may be exerted, at least in part, by inhibition of glial activation.Background: Although electroconvulsive therapy (ECT) is regarded as one of the efficient treatments for intractable psychiatric disorders, the mechanism of therapeutic action remains unclear. Recently, many studies indicate that ECT affects the immune system, including the immune-related cells, such as microglia, astrocytes, and lymphocytes. Moreover, microglial and astrocytic activation has been implicated in postmortem brains of schizophrenia patients. We previously demonstrated that Gunn rats showed schizophrenia-like behavior and microglial activation in their brains. In this study we examined the effects of electroconvulsive shock (ECS), an animal counterpart of ECT, on schizophrenia-like behavior, microgliosis and astrogliosis in the hippocampus of Gunn rats. Methods: The rats were divided into 4 groups, i.e., Wistar sham, Wistar ECS, Gunn sham and Gunn ECS. ECS groups received ECS once daily for 6 consecutive days. Subsequently, prepulse inhibition test (PPI) was performed on all animals. After PPI, immunohistochemistry analysis was carried out to determine microglial activation and astrocytic activation, using anti-CD11b and antiGFAP antibody, respectively. Results: We found PPI deficit in Gunn rats compared to Wistar rats, and it was significantly improved by ECS. In immunohistochemistry analysis revealed that there is significant higher expression of CD11b and GFAP in Gunn rats compared to Wistar rats. ECS attenuated the expression of both CD11b and GFAP in Gunn rats. The effect of ECS on the number of microglia in the hippocampus will be shown in the poster presentation. Conclusion: Our findings indicate that ECS ameliorates schizophrenia-like behavior in Gunn rats and attenuates both microglial activation and astrocytic activation in the hippocampus of Gunn rats. Accordingly, therapeutic effects of ECT may be exerted, at least in part, by inhibition of glial activation. PM376 Mountain-cultivated ginseng attenuates phencyclidine (PCP)-induced schizophrenia-like psychosis in mice The-Vinh Tran1, Duy-Khanh Dang1, Thu-Hien Thi Tu1, Eun-Joo Shin1, Sung Kwon Ko2, Kiyofumi Yamada3, Toshitaka Nabeshima4, HyoungChun Kim1 1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200–701, Republic of Korea; 2Department of Oriental Medical Food & Nutrition, Semyung University, Jecheon 27136, Republic of Korea; 3Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine; 4Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan Abstract Objective: Escalating evidence indicated that ginseng treatment protects memory deficit and psychotic behaviors. Although the underlying mechanism of schizophrenia remains elusive, oxidative stress induced by glutathione (GSH) loss might be involved in the pathogenesis of this disorder. We have selected mountain-cultivated ginseng (MG) out of various ginseng extracts to investigate firstly effect of ginsenosides on the psychosis induced by PCP Method: PCP (10 mg/kg/day, s.c.) was administered for consecutive 14 days. Novel object recognition-, forced swimming-, andObjective: Escalating evidence indicated that ginseng treatment protects memory deficit and psychotic behaviors. Although the underlying mechanism of schizophrenia remains elusive, oxidative stress induced by glutathione (GSH) loss might be involved in the pathogenesis of this disorder. We have selected mountain-cultivated ginseng (MG) out of various ginseng extracts to investigate firstly effect of ginsenosides on the psychosis induced by PCP Method: PCP (10 mg/kg/day, s.c.) was administered for consecutive 14 days. Novel object recognition-, forced swimming-, and social interaction-tests were performed 7 days after withdrawal from PCP. In addition, behavioral sensitization to an acute challenge of PCP (3 mg/kg, s.c.) was evaluated. The parameter of oxidative stress and GSH-dependent system were examined in the prefrontal cortex (PFC). MG (200 mg/kg/day, i.p.) was administered throughout the whole experimental period. Result: Repeated treatment with PCP significantly increased the immobility time in the forced swimming test and behavioral sensitization, while PCP significantly decreased the interaction time in the social interaction test and the novel object exploration in the novel object recognition test. Consistently, the oxidative stress was significantly increased, while GSH was significantly decreased in the PFC by repeated PCP treatment. MG significantly attenuated the behavioral abnormalities and oxidative damage induced by PCP. Conclusion: MG attenuates PCP-induced schizophrenia-like psychosis in mice through enhancing antioxidant potentials [This study is supported by a grant (Project No.S111415L020100) of the ‘Forestry Technology Projects’ provided by the Korea Forest Service].