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Ablation of Mrds1/Ofcc1 induces hyper-?-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.

ABSTRACT: Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as "the Japan Mouse Clinic". No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum ?-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-?-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-?-glutamyl transpeptidasemia and schizophrenia.

SUBMITTER: Ohnishi T

PROVIDER: S-EPMC3248446 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Ablation of Mrds1/Ofcc1 induces hyper-γ-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.

Ohnishi Tetsuo T Yamada Kazuo K Watanabe Akiko A Ohba Hisako H Sakaguchi Toru T Honma Yota Y Iwayama Yoshimi Y Toyota Tomoko T Maekawa Motoko M Watanabe Kazutada K Detera-Wadleigh Sevilla D SD Wakana Shigeharu S Yoshikawa Takeo T

PloS one 20111229 12

Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abno ...[more]

PMID: 22242126

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Project description:Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions.SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions.

Dataset Information

Ablation of Mrds1/Ofcc1 induces hyper-?-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.

Publications

Ablation of Mrds1/Ofcc1 induces hyper-γ-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.

Similar Datasets

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