Autism Spectrum Disorder Induced Pluripotent Stem Cells Display Dysregulated Calcium Signaling During Neural...

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Autism Spectrum Disorder (ASD) is a neurodevelopmental condition impacting communication and behavior.
• Dysregulation of Calcium (Ca²⁺) signaling is implicated in ASD pathophysiology.
• Induced pluripotent stem cells (iPSCs) offer a model to study ASD neurodevelopmental processes.

Purpose of the Study:

• To investigate transcriptomic and functional Ca²⁺ dynamics in neurons derived from ASD and control iPSCs.
• To compare Ca²⁺ signaling at different differentiation stages: iPSC, neural induction, neurosphere, and differentiated cortical neurons.
• To identify specific Ca²⁺ signaling alterations contributing to ASD.

Main Methods:

• Utilized idiopathic ASD and control iPSC lines.
• Employed dual SMAD inhibition for differentiation into cortical neurons.
• Performed bulk RNA sequencing across differentiation stages (iPSC, NI, NSP, Diff).
• Conducted Ca²⁺ imaging studies on iPSC and differentiated neuron stages.

Main Results:

• Transcriptomic analysis revealed more Ca²⁺ signaling genes differentially expressed in ASD iPSCs and differentiated neurons.
• ASD iPSCs showed elevated Ca²⁺ responses to ATP compared to controls.
• ASD differentiated neurons exhibited reduced Ca²⁺ response to ATP but increased responses to KCl and DHPG.

Conclusions:

• Aberrant calcium homeostasis is a key feature in the pathophysiology of ASD neurons.
• Functional Ca²⁺ signaling dysregulation occurs during neurogenesis in idiopathic ASD.
• These findings highlight the role of calcium signaling in ASD neurodevelopmental trajectories.