Abstract
Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here we provide evidence that primary hippocampal neurons from a mouse model of 22q11.2 deletion (Df(16)A+/− mice) have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits were prevented by introduction of the enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene in the 22q11.2 locus, and they were also observed in primary cultures from Zdhhc8-deficient mice. Many of these deficits were also present in the hippocampi of adult Df(16)A+/− and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.
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Acknowledgements
We thank M. Sribour, A. Abrams-Downey, A. Garçia-Williams and D. Swor for technical support and assistance with the mouse colony; and G. Feng (Duke University) and P. Scheiffele (Columbia University) for constructs. This research was supported in part by the US National Institutes of Health (MH67068 to M.K. and J.A.G. and MH077235 to J.A.G.), a McKnight Brain Disorders Award, an EJLB Scholar award (to J.A.G.) and two NARSAD awards (to J.A.G. and J.M.).
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J.M., A.D., L.J.D. and L.C. conducted research; K.L.S. contributed reagents; J.M., A.D., L.J.D., L.C. and A.B.M. analyzed data; M.K. and J.A.G. supervised the project; and J.M., A.D., L.J.D., A.B.M., M.K. and J.A.G. wrote the paper.
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Mukai, J., Dhilla, A., Drew, L. et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci 11, 1302–1310 (2008). https://doi.org/10.1038/nn.2204
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DOI: https://doi.org/10.1038/nn.2204
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