Missense mutation of the reticulon-4 receptor alters spatial memory and social interaction in mice

The reticulon-4 receptor, encoded by RTN4R, limits axonal sprouting and neural plasticity by inhibiting the outgrowth of neurites. Human association studies have implicated mutations in RTN4R in the development of schizophrenia, including the identification of several rare nonconservative missense mutations of RTN4R in schizophrenia patients. To investigate the effects of missense mutation of the reticulon-4 receptor on phenotypes relevant to schizophrenia, we behaviourally characterized a novel Rtn4r mutant mouse line with an amino acid substitution (R189H) in the Nogo-66 binding site. Behavioural assays included prepulse inhibition of acoustic startle, locomotor activity, social interaction and spatial cognition. When compared with wildtype littermates, Rtn4r mutant mice exhibited greater social preference, which may reflect a social-anxyolitic effect, and a mild impairment in spatial cognition. Given the mild effect of the R189H mutation of Rtn4r on behavioural phenotypes relevant to schizophrenia, our results do not support missense mutation of RTN4R as a strong risk factor in the pathogenesis of schizophrenia.

► First study to examine an in vivo characterization of a point mutation in Rtn4r in the mouse as it related to the development of schizophrenia.
► Behavioural assays included prepulse inhibition of acoustic startle, locomotor activity, social interaction and spatial cognition.
► Rtn4r mutant mice exhibited greater social preference, which may reflect a social-anxyolitic effect, and a mild impairment in spatial cognition.
► Results do not support missense mutation of RTN4R as a strong risk factor in the pathogenesis of schizophrenia.