Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion

SUMMARY 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 22q11.2 deletion mouse model [Df(16)A+/−] have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits can be prevented by introduction of enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene located in the 22q11.2 locus and they are also observed in primary cultures from Zdhhc8-deficient mice. We show that many of these deficits are also present in the hippocampus 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.