Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure

Background

Variation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia (SCZ) and bipolar disorder (BP). Evidence suggests that ZNF804A is a regulator of gene transcription and is present in nuclear and extranuclear compartments. However, a detailed examination of ZNF804A distribution and its neuronal functions has yet to be performed.

Methods

The localization of ZNF804A protein was examined in neurons derived from human neural progenitor cells (hNPCs), human induced pluripotent stem cells (hiPSCs) or in primary rat cortical neurons. Additionally, siRNA-mediated knockdown of ZNF804A was conducted to determine its role in neurite formation, maintenance of dendritic spine morphology and responses to activity-dependent stimulations.

Results

Endogenous ZNF804A protein localized to somato-dendritic compartments and co-localized with the putative synaptic markers in young neurons derived from hNPCs and hiPSCs. In mature rat neurons, Zfp804A, the homolog of ZNF804A, was present in a subset of dendritic spines and co-localized with synaptic proteins in specific nanodomains, as determined by superresolution microscopy. Interestingly, knockdown of ZNF804A attenuated neurite outgrowth in young neurons, an effect potentially mediated by reduced neuroligin-4 (NLGN4) expression. Furthermore, knockdown of ZNF804A in mature neurons resulted in the loss of dendritic spine density, and impaired responses to activity-dependent stimulation.

Conclusions

These data reveal a novel subcellular distribution for ZNF804A within somato-dendritic compartments and a nanoscopic organisation at excitatory synapses. Moreover, our results suggest that ZNF804A plays an active role in neurite formation, maintenance of dendritic spines and activity-dependent structural plasticity.