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Synaptic modulators Nrxn1 and Nrxn3 are disregulated in a Disc1 mouse model of schizophrenia

Molecular Psychiatry volume 16, pages 585–587 (2011)Cite this article

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A Corrigendum to this article was published on 26 March 2012

DISC1 is a leading candidate gene for schizophrenia and related disorders. It has several modes of action through protein–protein interaction at multiple cellular locations, including the synapse.1, 2 Previously, we developed and characterised a mouse line carrying an ENU-induced Disc1 missense mutation, L100P. The mice exhibit behavioural, anatomical and pharmacological phenotypes related to schizophrenia; schizophrenia-like endophenotypes, including deficits in pre-pulse inhibition, latent inhibition and working memory, and, at the molecular level, reduced DISC1–PDE4B interaction.3 Here, we show that the L100P mutation disregulates expression of the synaptic modulators Nrxn1 and Nrxn3 at key points during development, as well as in the adult mouse. Nrxn1 is involved in maintenance of synaptic junctions and is a mediator of intracellular signalling, modulating maturation and differentiation of synapses.4 Nrxn3 is a membrane protein involved in cell adhesion, synaptic transmission and neurotransmitter secretion.4

Both the Neurexin gene family and DISC1 have been independently implicated in schizophrenia and autism. A missense mutation and copy number variants in NRXN1 were first linked to autism (ref. 5 and references within), and copy number variants in this gene were subsequently reported to be more abundant in schizophrenia than in controls (ref. 6 and references within). Recent pathway analysis of the genes identified by three large genome-wide association studies of bipolar disorder and schizophrenia (ISC, GAIN and WTCCC) suggested that perturbation of cell adhesion molecules may be central to development of neuropsychiatric illness and, furthermore, identified NRXN1 as being one of two genes associated in all three studies.7 The role of DISC1 in schizophrenia and bipolar disorder is well established,1 but a number of recent studies of autism spectrum disorders have found association between DISC1 variants and these conditions also (ref. 8 and references within).

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Authors and Affiliations

  1. Psychiatric Genetics, Medical Genetics Section, Centre for Molecular Medicine and Institute of Genetics and Molecular Medicine, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK

    S M Brown, J K Millar, H S Torrance, S M Anderson, R Walker, A Rampino, P A Thomson, D J Porteous & K L Evans

  2. Centre for Cognitive Ageing and Cognitive Epidemiology, Medical Genetics Section, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK

    S J Clapcote

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Ave., Toronto, ON, Canada

    J C Roder

  4. Institute of Membrane and Systems Biology, University of Leeds, Leeds, UK,

    P A Thomson, D J Porteous & K L Evans

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  1. S M Brown
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Correspondence to S M Brown.

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Brown, S., Clapcote, S., Millar, J. et al. Synaptic modulators Nrxn1 and Nrxn3 are disregulated in a Disc1 mouse model of schizophrenia. Mol Psychiatry 16, 585–587 (2011). https://doi.org/10.1038/mp.2010.134

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