Guy A. Rouleau,
Professor, Department of Neurology & Neurosurgery, McGill University
The first part of the presentation will focus on the investigation into the mechanisms underlying the neuronal hyperexcitability phenotype observed in iPSC-derived neurons from patients with bipolar disorder (BD). This segment will reveal the selective effects of lithium through the Akt and AMPK pathways and will propose innovative therapeutic strategies tailored for both lithium-responsive and non-responsive patients. The second part will address the translational potential of these cellular phenotypes by exploring extracellular vesicles (EVs) as a source of clinically accessible biomarkers. We will present evidence that EVs derived from patient neurons carry distinct protein and miRNA signatures associated with BD and lithium responsiveness. Functional assays further indicate that BD-derived secreted factors can modulate neuronal network activity, supporting a mechanistic link between EV cargo and disease-relevant phenotypes.
Finally, the presentation will introduce recent efforts to move beyond lithium by identifying more selective therapeutic strategies targeting the hyperexcitability phenotype. By combining cell surface proteomics, synaptic fractionation, electrophysiology, and calcium imaging, we are identifying ion channels and synaptic proteins that drive early network hyperexcitability in BD neurons. We then test whether pharmacological targeting of these candidates can normalize neuronal activity, providing a rational framework for the development of more specific and potentially better-tolerated treatments.
Together, this work illustrates a translational pipeline from patient-derived cellular models to biomarker development and mechanism-based therapeutics, advancing a precision medicine approach to bipolar disorder.
Author List: Anouar Khayachi, Malak Abuzgaya, Alessia Pietrantonio, Yumin Liu, Austen Milnerwood, Martin Alda, Guy Rouleau
Lena Nechayeva
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