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Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3ζ deficiency

Abstract

Complex neuropsychiatric disorders are believed to arise from multiple synergistic deficiencies within connected biological networks controlling neuronal migration, axonal pathfinding and synapse formation. Here, we show that deletion of 14-3-3ζ causes neurodevelopmental anomalies similar to those seen in neuropsychiatric disorders such as schizophrenia, autism spectrum disorder and bipolar disorder. 14-3-3ζ-Deficient mice displayed striking behavioural and cognitive deficiencies including a reduced capacity to learn and remember, hyperactivity and disrupted sensorimotor gating. These deficits are accompanied by subtle developmental abnormalities of the hippocampus that are underpinned by aberrant neuronal migration. Significantly, 14-3-3ζ-deficient mice exhibited abnormal mossy fibre navigation and glutamatergic synapse formation. The molecular basis of these defects involves the schizophrenia risk factor, DISC1, which interacts isoform specifically with 14-3-3ζ. Our data provide the first evidence of a direct role for 14-3-3ζ deficiency in the aetiology of neurodevelopmental disorders and identifies 14-3-3ζ as a central risk factor in the schizophrenia protein interaction network.

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Acknowledgements

We thank Rebecca Krake for genotyping mice, aiding in behavioural studies, and maintaining the mouse colonies, Daniel Thomas for criticizing the paper and Thomas Sullivan for help with statistical analysis. This work was funded by grants from the National Health and Medical Research Council of Australia and Medvet Laboratories. HSR is the recipient of the Peter Nelson Leukaemia Research Fellowship and QS is the recipient of a National Health and Medical Research Council of Australia Career Development Award.

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Correspondence to A F Lopez or Q P Schwarz.

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Cheah, PS., Ramshaw, H., Thomas, P. et al. Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3ζ deficiency. Mol Psychiatry 17, 451–466 (2012). https://doi.org/10.1038/mp.2011.158

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Keywords

  • neurodevelopment
  • neuropsychiatric disorder
  • schizophrenia
  • synapse
  • 14-3-3ζ

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