It’s out! “Neuronal defects in a human cellular model of 22q11.2 deletion syndrome” in which we used 3D human cortical spheroids neurons to study the pathways linked to neuropsychiatric disease in 22q11.2 deletion. rdcu.be/b7N8D
https://twitter.com/themasap/status/1310671122468282368
This work was a great collaboration with my co-first authors @themasap and @omerevah. A result of a vast collaboration between @PascaStanford @GeschwindLab @HuguenardLab @rdolmetsch @Winkytheelf, Porteus, Nishino, and Hallmayer labs.
22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. 1 in 4 22q11.2DS patients develop psychosis,
which corresponds to a 20-fold increase in risk and accounts for 1–2% of all SCZ cases.
which corresponds to a 20-fold increase in risk and accounts for 1–2% of all SCZ cases.
In 3D cortical brain organoids from these patients, we found significant changes in genes related to neuronal excitability, regulation of calcium transport, calcium signaling, resting membrane potential and voltage-gated calcium channel activity.
Following up on the gene expression results, we discovered that an elevated resting membrane potential causes voltage-dependent inactivation of calcium channels which resulted in reduced intracellular Ca2+ in 22q11 neurons.
When we looked at how calcium, an important ion important for regulating neuronal function, we discovered that 22q11DS neurons had a decreased influx of calcium upon depolarization!
We wondered why and found a potential culprit – DGCR8, one of the genes in the 22q11.2 deletion region, which is important for processing micro-RNAs, is involved!
In a CRISPR-Cas9 single allele knockout of DGCR8 in an iPSC line, we found similar cellular changes to those seen in 22q11DS neurons, including increased spontaneous activity and decreased Ca2+ flux following depolarization.
Overexpression of DGCR8 was able to rescue these functional phenotypes in DGCR8 and 22q11DS neurons.
Finally, acute treatment with several antipsychotic drugs, including raclopride, sulpiride and olanzapine, was able to rescue the deficit in intracellular calcium and restore the resting membrane potential!
A big thank you to all the families who participated in this study. We truly appreciate you!
And of course, this work was made possible by funding from @CIRM @NIH @NIMHgov @BBRFoundation @AutismScienceFd @NSF @nyscf @czi @StanfordBrain
• • •
Missing some Tweet in this thread? You can try to
force a refresh
