Calcium-Channel Abnormalities Underlie Genetic Cause Of Schizophrenia

In 22q11.2 deletion syndrome, a common genetic cause of schizophrenia, abnormalities in calcium-channel signaling resulting from the loss of the gene DGCR8 appear to underlie the neuronal defects, researchers report.

"I think this study is bringing us closer to understanding the molecular and cellular mechanisms in neurons from patients with neuropsychiatric disease, and by doing so they are pointing to potential new therapeutic targets," Dr. Sergiu P. Pasca of Stanford University, in California, told Reuters Health by email.

The 22q11.2 deletion syndrome is associated with an estimated 20-fold increase in the risk of schizophrenia and confers a 30% to 40% risk for autism-spectrum disorder (ASD). The functional neuronal defects in people with 22q11.2 deletion syndrome have not been investigated.

To investigate, Dr. Pasca and colleagues generated pluripotent stem cells from 15 individuals with 22q11.2 deletion syndrome and 15 control individuals and differentiated them into three-dimensional cerebral cortical organoids.

Transcriptional analyses performed over 100 days of 3D differentiation identified changes that might be related to the loss of the 22q11.2 locus gene DGCR8, as well as enrichment for genes related to mitochondrial function and neuronal excitability (including genes related to regulation of calcium transport, calcium signaling, and resting membrane potential (RMP) or voltage-gated calcium channel activity).

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22q11.2 deletion syndrome was not, however, associated with major defect in corticogenesis.

The researchers used CRISPR/Cas9 to introduce a heterozygous loss of DGCR8 into neurons, and this loss was associated with recapitulation of the abnormal function seen in 22q11.2 deletion syndrome neurons, they report in Nature Medicine.

These functional defects were reversed by restoring DGCR8 or by DGCR8 overexpression and by treatment with the antipsychotics raclopride, sulpiride and olanzapine.

The data suggest that these three antipsychotic drugs likely rescue the 22q11.2 deletion syndrome defect by restoring RMP in cortical neurons, the researchers say.

"The fact that putting back the gene DGCR8 could restore neuronal defects in 22q11.2 deletion syndrome speaks to the role that this gene and downstream microRNAs at fault may have in finding new therapeutics," Dr. Pasca said.

"I would like to emphasize also that the transcriptional and physiological data in 22q11 deletion syndrome (22q11DS) neurons suggest a link at the cellular level between several pathways that have been independently associated with neurodevelopmental disorders in previous studies," he said. "For instance, the transcriptional changes in 22q11DS neurons are also enriched for genes associated with increased risk for schizophrenia and autism. It is therefore possible that, similar to 22q11DS, other disorders on the schizophrenia or autism spectrum may display convergence of multiple signaling defects in pathways suggested by genetic studies."

"Given the distinct clinical phenotypes of schizophrenia and ASD, it will be interesting to expand this work in a larger sample to determine whether one can distinguish molecular pathways unique to each clinical condition, as well as to identify the potential contribution of genetic background, including polygenic risk for schizophrenia," the authors note.

"Genetic forms of schizophrenia open an opportunity to begin addressing the heterogeneity of neuropsychiatric disorders and to identify neuronal phenotypes associated with complex disorders," Dr. Pasca concluded.

—Will Boggs MD

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