Functional characterization and pharmacological targeting of calcium signaling pathways for the treatment of autism spectrum disorders

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. An increasing number of genetic variants implicated in ASD has been reported so far, suggesting a high degree of locus heterogeneity and a contribution from rare and de novo variants. Calcium signaling is essential for many aspects of neuronal function. Dysregulation of calcium signaling has been implicated in several neurological disorders, including ASD. Risk variants associated with ASD converge on calcium signaling, and can cause the defect in calcium signaling of neurons. However, it remains poorly understood how calcium dysregulation gives rise to the pathophysiology of ASD and how to intervene calcium signaling as a therapeutic target for ASD. Objectives: We aim to study the pathophysiological mechanisms underlying ASD phenotype using patient‐specific human induced pluripotent stem cell (hiPSC)‐derived neurons with focus on calcium signaling. Pathogenic genetic variants in VGCC and SOCE can lead to the onset of a variety of neurological diseases. QBRI has identified six variants in ASD risk genes related to calcium signaling from the local Qatari population including calcium and potassium channels. Our goal is to study i) how these genetic mutations of ASD risk genes found in individuals from the Qatar population lead to the defect in calcium signaling and neuronal activity as the pathophysiology of ASD and ii) screen drugs that rescue calcium signaling for development of ASD therapeutic using hiPSC‐derived cortical neurons and zebrafish as a disease model system of ASD. Methods: The major impediment to ASD research is to produce relevant animal and cellular models. We will generate ASD-specific hiPSC‐derived cortical neurons as a disease model. Patient-specific hiPSC-derived neurons recapitulate the genomic, molecular and cellular attributes of developing native human neuronal subtypes with advantages over single time point studies. Dr. Lawrence Stanton’s team will generate patient-specific human neurons. Dr. Ayman’s group will conduct a high throughput drug screen of an FDA-approved library using an automatic assay system for drug screening. Dr. Sahar Da’as will generate patient’s specific zebrafish animal models to investigate the underlying mechanisms of ASD and its effects on behavior. My team will carry out functional assays to study the pathophysiology using calcium imaging and electrophysiological recording that include whole-cell patch clamping and micro-electrode array (MEA) for neuronal activity and neural network in both cellular and zebrafish models. Finally, we will screen drugs that intervene SOCE and calcium signaling for development of ASD therapeutic. Significance: Modeling ASD using patient-specific hiPSC-derived neurons can provide a platform to study the pathophysiological mechanisms of ASD, and will be a valuable tool to develop therapies for ASD.

Hamad Bin Khalifa University (HBKU)