Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome

Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca(v)1.2. Here, we find that acute pharmacological modulation of Ca(v)1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced gamma-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by intemeuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.

Automated summary

In this study, it was found that the role of L-type calcium channel in neurodevelopmental diseases is complex, as it can regulate the saltation length and frequency of interneuron migration. Inhibition of GABA-A receptors can restore the defect in migration frequency, while modulation of actomyosin and myosin light chain phosphorylation can improve the defect in saltation length.