Constitutive genetic deletion of the growth regulator nogo-A induces schizophrenia-related endophenotypes

Roman Willi, Oliver Weinmann, Christine Winter, Julia Klein, Reinhard Sohr, Lisa Schnell, Kay Yan Benjamin Yee, Joram Feldon, Martin E. Schwab

Research output: Journal article publicationJournal articleAcademic researchpeer-review

44 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)556-567
Number of pages12
JournalJournal of Neuroscience
Volume30
Issue number2
DOIs
Publication statusPublished - 13 Jan 2010
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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