Molecular Substrates of Altered Axonal Growth and Brain Connectivity in a Mouse Model of Schizophrenia

Abstract

Summary 22q11.2 deletion carriers show specific cognitive deficits and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A+/− mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

“…Abnormal neuronal alignments have been reported in neuropsychiatric disorders associated with cognitive impairments, such as schizophrenia (55) and autism (56). Interestingly, defective axonal terminal branching that is similar to the impaired corticocortical axonal branching observed in our study has recently been demonstrated in an animal model of schizophrenia (57), lending support to the notion that the impaired corticocortical wiring in brain disorders could cause cognitive impairments.…”

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…A subsequent study demonstrated that dhhc8-deficient mice showed a decrease in dendritic spine density [239] and disruption of axonal growth [240]. In contrast to the studies described above, several studies have demonstrated no association between dhhc8 gene and susceptibility to schizophrenia [236,[241][242][243][244][245][246].…”

“…An association between dhhc8 and schizophrenia could be restricted in closely linked genetic locus based on specific ethnic groups or dhhc8 might be indirectly implicated in schizophrenia. In a 22q11.2-deletion mouse model of schizophrenia Df(16)A +/− mice, axonal growth and branching was disrupted in vivo and these deficits were rescued when DHHC8 was exogenously expressed in the mice [240]. In addition, a schizophrenia-related circuit, a prefrontal cortexhippocampus connectivity and spatial working memory were impaired in dhhc8-deficient mice.…”

Делеція 22q11.2 хромосоми: світові критерії визначення, стандарти діагностики та моніторингу

“…TBX1 -найбільш вивчений ген у ре-гіоні делеції 22q11.2, гетерозиготи з мутаціями TBX1 мають кардіоваскулярні дефекти, аплазію або гіпо-плазію тимуса та паращитоподібних залоз, гетеро-зиготи за геном DGCR8 -вади розвитку нервової системи. Існують і інші мутації генів LCRs 22q11.2, пов'язані із захворюваннями, щодо більшості яких тривають дослідження на моделях тварин [6,7].…”