Studying the neuropsychiatric spectrum of Timothy Syndrome, from cells to patients

Sergiu Pasca, MD, Associate Professor of Psychiatry and Behavioral Sciences and
Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis

Rebecca Levy, MD, PhD, Instructor, Child Neurology and Neurogenomics, Lucile Packard Children’s Hospital at Stanford University

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A critical challenge in understanding the biological mechanisms of neuropsychiatric disorders and finding therapeutics is the lack of direct access to brain cells from
patients.

To address this, the Pasca laboratory at Stanford University has developed novel approaches to generate, non-invasively, human neurons and glial cells^* from patients in 3D cultures known as brain region-specific organoids and assembloids.

Using stem cells derived from patients with Timothy Syndrome, Dr Pasca and his team have uncovered changes in the way cells handle calcium as well as defects in the generation of specific cells types in the brain, their morphology and patterns of migration^#.

More work is needed to uncover the detailed mechanism by which mutations in
CACNA1C lead to disease in patients with Timothy Syndrome. How do different
mutations (typical and atypical) contribute to neuronal dysfunction? Are these changes in neurons reversible? How do neuronal changes correlate to neuropsychiatric disease in patients?

The laboratory is now interested in recruiting families of patients with Timothy Syndrome to learn more about the neuropsychiatric symptoms of the disease, their evolution over time and how this may be related to specific mutations in CACNA1C.

* Glial cells are present in the nervous system but are not neurons (the electrically active nervous system cells). Glial cells perform a variety of non-signaling functions such as removing waste products, providing support to and nourishing the neurons; through these, glial cells maintain an appropriate environment for normal neuronal function.

# During development, neurons migrate from the area where they proliferate (i.e. divide to make new cells) to their final position; neuronal migration is crucial for normal brain development as it brings cells into appropriate spatial relationships with one another, enabling them to interact appropriately.