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A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes
Roman Willi1, Oliver Weinmann, Christine Winter
1Brain Research Institute, University of Zurich, Zurich, Switzerland. rwilli@hifo.uzh.ch
Abstract:
The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders.
Insights
Lifelong absence of Nogo-A protein in mice caused schizophrenia-like behaviors, suggesting a role in neurodevelopment. This indicates Nogo-A may be an etiological factor in neuropsychiatric disorders like schizophrenia.
Area of Science:
- Neuroscience
- Neurobiology
- Developmental Neuroscience
Background:
- Nogo-A protein inhibits neurite outgrowth and regeneration in the central nervous system (CNS).
- Abnormal Nogo-A expression or Nogo receptor (NgR) mutations are implicated in the genetic risk for neuropsychiatric disorders, including schizophrenia.
Purpose of the Study:
- To investigate if Nogo-A gene deletion leads to schizophrenia-like abnormalities in a mouse model.
- To explore the role of Nogo-A in neurodevelopment and its potential contribution to neuropsychiatric disorders.
Main Methods:
- Systemic, lifelong knockout of the Nogo-A gene in mice.
- Behavioral assessments including sensorimotor gating, latent inhibition, perseverative behavior, and amphetamine sensitivity.
- Analysis of monoaminergic transmitter levels and dopamine D2 receptor expression in striatal and limbic regions.
- Acute antibody-mediated Nogo-A neutralization in adult wild-type mice.
Main Results:
- Nogo-A knockout mice exhibited schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased amphetamine sensitivity.
- Altered monoaminergic transmitter levels and dopamine D2 receptor expression were observed in specific brain regions of knockout mice.
- Elevated expression of growth-related markers was associated with Nogo-A deletion.
- Acute Nogo-A neutralization in adult mice did not produce these phenotypes, suggesting a developmental origin.
Conclusions:
- Nogo-A plays a critical role in normal neurodevelopment.
- Lifelong Nogo-A deficiency can induce schizophrenia-like behavioral and neurochemical abnormalities.
- Alterations in Nogo-A expression may represent an etiological factor in schizophrenia and related neuropsychiatric disorders.
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