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Effects of genetic and environmental risk for schizophrenia on hippocampal activity and psychosis-like behavior in mice.

ABSTRACT: Schizophrenia is a serious mental illness most notably characterized by psychotic symptoms. In humans, psychotic disorders are associated with specific hippocampal pathology. However, animal model systems for psychosis often lack this pathology, and have been weak in providing a representation of psychosis. We utilized a double-risk model system combining genetic risk with environmental stress. We hypothesized these factors will induce hippocampal subfield pathology consistent with human findings, as well as behavioral phenotypes relevant to psychosis. To address this, we exposed wild-type and transgenic Disc1 dominant negative (Disc1-deficient) mice to maternal deprivation. In adulthood, hippocampal subfields were examined for signs of cellular and behavioral pathology associated with psychosis. Mice exposed to maternal deprivation showed a decrease in dentate gyrus activity, and an increase in CA3/CA1 activity. Furthermore, results demonstrated a differential behavioral effect between maternal deprivation and Disc1 deficiency, with maternal deprivation associated with a hyperactive phenotype and impaired prepulse inhibition, and Disc1 deficiency causing an impairment in fear conditioning. These results suggest distinct consequences of environmental and genetic risk factors contributing to psychosis, with maternal deprivation inducing a state more wholly consistent with schizophrenia psychosis. Further research is needed to determine if this pathology is causally related to a specific behavioral phenotype. The development of a strong inference animal model system for psychosis would satisfy a high medical need in schizophrenia research.

SUBMITTER: Scott D

PROVIDER: S-EPMC5783549 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Effects of genetic and environmental risk for schizophrenia on hippocampal activity and psychosis-like behavior in mice.

Scott Daniel D Tamminga Carol A CA

Behavioural brain research 20171115

Schizophrenia is a serious mental illness most notably characterized by psychotic symptoms. In humans, psychotic disorders are associated with specific hippocampal pathology. However, animal model systems for psychosis often lack this pathology, and have been weak in providing a representation of psychosis. We utilized a double-risk model system combining genetic risk with environmental stress. We hypothesized these factors will induce hippocampal subfield pathology consistent with human finding ...[more]

PMID: 29155005

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Project description:The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

Dataset Information

Effects of genetic and environmental risk for schizophrenia on hippocampal activity and psychosis-like behavior in mice.

Publications

Effects of genetic and environmental risk for schizophrenia on hippocampal activity and psychosis-like behavior in mice.

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