Abstract: There is a pressing need to develop novel and effective treatments for depression and anxiety disorders, which impact a significant portion of the global population. Neurotherapeutic psychedelic compounds offer a promising solution due to their rapid and enduring effects on synaptic plasticity and behavior. While their clinical efficacy is under investigation, the precise mechanisms by which acute treatments lead to long-term structural and functional changes remain poorly understood. For instance, the balance between excitation and inhibition (E/I) plays a critical role in shaping cortical circuitry and is implicated in numerous neuropsychiatric and neurodevelopmental disorders. However, the spatio-temporal mechanisms by which excitatory and inhibitory activity regulate circuit refinement across developmental windows are not well characterized. Emerging evidence suggests that compounds such as 5-MeO-DMT can alter the expression of over 900 proteins, including those involved in cytoskeletal dynamics, neural network formation, and neuroimmune communication. To address these gaps, my research will investigate the molecular impact of serotonergic psychedelic compounds on the synaptic development of cortical organoids derived from human induced pluripotent stem cells (iPSCs). Specifically, I will examine the biochemical pathways that regulate E/I balance and synaptic development across different stages of organoid maturation. To achieve this, I will employ state-of-the-art techniques, including optogenetics combined with multi-electrode array (MEA) recordings, to monitor immediate and long-term molecular and physiological changes. Additionally, transcriptomic analysis and immunofluorescence imaging will be used to evaluate neurite growth and synaptic connectivity. This research aims to identify critical periods during which neural circuits are most susceptible to disruptions in E/I balance and determine how these vulnerabilities differ across neurodevelopmental stages, such as axon guidance and synaptic formation.
Funding Source: The Human Frontier Science Program (HFSP), The Brain and Behavior Research Foundation (BBRF), The California Institute for Regenerative Medicine (CIRM)
