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.
Highlights
Alterations in intracellular calcium signaling have been linked to neuropsychiatric disease
To determine the timing of Timothy syndrome (TS) mutant exon expression and the precise developmental window during which the TS mutation exerts its cellular phenotypes, we investigated the expression of Cacna1c exon 8A and its mutually exclusive alternate exon 8 during mouse and human corticogenesis
We first measured the relative abundance of exons 8A and 8 using quantitative reverse transcription PCR on RNA extracted from dissected mouse frontal cortices at eight time points spanning embryonic and postnatal corticogenesis (Figure 1—figure supplement 1a–c)
Summary
Alterations in intracellular calcium signaling have been linked to neuropsychiatric disease. Genetic variants in calcium signaling proteins and voltage-gated calcium channel subunits, including the pore-forming a and auxiliary b subunits of Cav1.2, have been associated with disorders such as ASD, schizophrenia, and attention deficit hyperactivity disorder (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013). These studies strongly implicate genetic changes in Cav1.2 in multiple psychiatric disorders, little is known about how Cav1.2 affects core cellular and molecular processes to contribute to the development of neuropsychiatric disorders
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