title: Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes.
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.
authors.affiliation: Brain Research Institute, University of Zurich, Zurich, Switzerland. rwilli@hifo.uzh.ch
authors.forename: Roman
authors.initials: R
authors.lastname: Willi
authors.forename: Oliver
authors.initials: O
authors.lastname: Weinmann
authors.forename: Christine
authors.initials: C
authors.lastname: Winter
authors.forename: Julia
authors.initials: J
authors.lastname: Klein
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sohr
authors.forename: Lisa
authors.initials: L
authors.lastname: Schnell
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
authors.forename: Joram
authors.initials: J
authors.lastname: Feldon
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007266:Inhibition, Psychological; D007398:Interpersonal Relations; D007858:Learning / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000172:deficiency* / Q000276:immunology / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D000070798:Nogo Proteins; D010641:Phenotype; D017397:Prefrontal Cortex / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D055139:Sensory Gating / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D000906:Antibodies; D000697:Central Nervous System Stimulants; D005904:Glial Fibrillary Acidic Protein; D009185:Myelin Proteins; D018377:Neurotransmitter Agents; D000070798:Nogo Proteins; D017448:Receptors, Dopamine D2; C000603201:Rtn4 protein, mouse; D000661:Amphetamine