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Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome
Georgia Panagiotakos1,2,3, Christos Haveles2,3, Arpana Arjun2,3,4
1Department of Neurobiology, Stanford University School of Medicine, Stanford, United States.
Abstract:
The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.
Insights
Timothy syndrome (TS), a form of autism spectrum disorder (ASD), stems from a Cav1.2 calcium channel mutation. This mutation disrupts normal neuronal development by altering calcium channel splicing patterns in the developing brain.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Timothy syndrome (TS) is a syndromic autism spectrum disorder (ASD) linked to a specific mutation in the Cav1.2 calcium channel.
- This mutation affects the alternatively spliced exon 8A, crucial for channel function during development.
Purpose of the Study:
- To investigate the impact of the TS-associated Cav1.2 mutation on neuronal differentiation during development.
- To elucidate the role of altered calcium channel splicing in the pathophysiology of syndromic ASD.
Main Methods:
- Utilized mouse brain models and human induced pluripotent stem cells (iPSCs) derived from TS patients.
- Analyzed Cav1.2 exon utilization patterns during neuronal differentiation.
- Assessed changes in specific neuronal populations (SATB2+, CTIP2+) in response to the mutation.
- Investigated the calcium-dependent effects of mutant Cav1.2 channels *in utero*.
Main Results:
- The TS mutation impairs a normal developmental switch in Cav1.2 exon splicing, leading to persistent expression of mutant channels.
- In iPSC models, the mutation resulted in a decrease of SATB2+ cortical neurons and an increase of CTIP2+ neurons.
- Expression of TS-Cav1.2 channels in embryonic mouse cortex mimicked these differentiation defects in a calcium-dependent manner.
- Both gain and loss of Cav1.2 function *in utero* reciprocally altered the balance of these neuronal populations.
Conclusions:
- Disruption of developmentally regulated calcium channel splicing patterns significantly alters cortical differentiation.
- These findings provide crucial *in vivo* insights into the pathophysiology of Timothy syndrome and potentially other syndromic ASDs.
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