Exploring calcium signaling defects in a mouse model of 16p11.2 deletion

Mutations in calcium channels and calcium-signaling proteins have been reproducibly linked to neurodevelopmental disorders, including autism spectrum disorders (ASD), underscoring essential roles for calcium-dependent signaling in the regulation of brain development. As a graduate student, Georgia Panagiotakos found that utilization of two ASD-relevant exons of the L-type calcium channel (LTC) Cav1.2 is dynamically regulated during corticogenesis, and that excess calcium influx through Cav1.2 caused by a gain of function missense mutation impairs the differentiation of cortical projection neuron subtypes. Similar to what she observed with gain of function of Cav1.2, in a previous SFARI funded project, Panagiotakos and her colleagues also found alterations in cortical neuron differentiation in a mouse model of 16p11.2 deletion¹. Imbalance of neuronal subtypes in the cortex has been described in several genetically defined psychiatric syndromes, and Panagiotakos’s findings lend support to the idea that alterations in the differentiation of specific neuronal types is more broadly associated with ASDs.

Panagiotakos now proposes to investigate defects in calcium signaling and neuronal fate specification in a mouse model of 16p11.2 deletion, with an eye toward defining core cellular and molecular hallmarks of ASD. Panagiotakos hypothesizes that differentiation defects observed in 16p11.2 deletion could be, in part, explained by calcium signaling defects in differentiating neural progenitor cells. This hypothesis will be tested in two ways: 1) through characterization of defects in fate specification in a mouse model of 16p11.2 chromosomal deletion, and 2) via interrogation of alterations in calcium signaling in a mouse model of 16p11.2 chromosomal deletion. The results from these studies will help define potential points of convergence in the emergence of cellular phenotypes underlying ASD.