Key Details
- Researchers at King's College London investigated the ZNF804A gene, a known risk factor for schizophrenia.
- The study was published in Science Advances on [not specified].
- The research used CRISPR-Cas9 to suppress ZNF804A activity in developing human glutamatergic neurons.
- Suppression of ZNF804A led to increased synaptic protein levels and heightened electrical excitability in these neurons.
- The neurons also showed increased local protein production in dendrites, linking two previously separate cellular processes associated with the gene.
Background
Schizophrenia is highly heritable and has a strong developmental component. Genomic studies have identified many genetic variants associated with the disorder, but the mechanisms linking these variants to neural changes remain unclear. ZNF804A was one of the first schizophrenia risk genes identified from genomic data, but its function was poorly understood.
What the Researchers Say
Professor Deepak Srivastava (joint senior author):
"While previous large-scale genetic studies have identified genetic risk factors for schizophrenia, they don't tell you when in development that gene is active or which cell type it's expressed in. To get at this information we needed to use precision functional genomics."
Dr Laura Sichlinger (first author):
"Schizophrenia is a highly complex disorder... There are 287 loci so far identified by genomic studies in humans. To be able to understand what the genes normally do in neurons is a step forward in understanding the biology of the disorder."
Professor Anthony Vernon (joint senior author):
"These specific genetic manipulations of developing neurons do not mimic the full complement of genetic risk linked to schizophrenia. Rather, they are a tool that allow us to understand what specific risk genes... control in a cell and developmental timepoint specific manner."
Significance
The findings provide a mechanistic link between a genetic risk factor for schizophrenia and cellular changes in developing neurons. This may inform future research into treatments targeting biological pathways affected by genetic risk variants.