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Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

Molecular Psychiatry volume 13, pages 661–672 (2008)Cite this article

Abstract

Phospholipase C-β1 (PLC-β1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-β1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-β1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-β1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene–environment interactions.

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Acknowledgements

We thank L Gray, J Nithianantharajah and C Hannan for comments on manuscript drafts. This work was supported by NHMRC project grants and an RD Wright award (AJH). AJH currently holds a Pfizer Australia Senior Research Fellowship. BD is an NHMRC Senior Research Fellow. ES is the Ronald Griffith Schizophrenia Research Fellow. Funding was also provided by Trust Company Australia (CEM).

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Authors and Affiliations

  1. Howard Florey Institute, University of Melbourne, Melbourne, VIC, Australia

    C E McOmish, E Burrows, M Howard & A J Hannan

  2. Mental Health Research Institute of Victoria, Melbourne, VIC, Australia

    E Scarr, B Dean & M van den Buuse

  3. Centre for Neuroscience, University of Melbourne, Parkville, VIC, Australia

    E Scarr

  4. Centre for Calcium and Learning, Korea Institute of Science and Technology, Seoul, South Korea

    D Kim & H-S Shin

  5. Department of Pathology, University of Melbourne, Melbourne, VIC, Australia

    B Dean

  6. Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia

    B Dean

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  1. C E McOmish
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Correspondence to A J Hannan.

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McOmish, C., Burrows, E., Howard, M. et al. Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Mol Psychiatry 13, 661–672 (2008). https://doi.org/10.1038/sj.mp.4002046

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