Blake Fordyce is a third-year PhD student in the Lab of Dr. Bryan Roth. Using advanced microscopy techniques and protein biochemistry, Blake focuses on studying the 5HT2A receptor and its response to psychedelics within its native cellular environment. Her current research employs super-resolution microscopy methods to detect receptor conformational states. Through this innovative approach, Blake explores psychedelic-induced conformational shifts and recruitment patterns of the 5HT2A receptor, contributing to a deeper understanding of potential therapeutic processes.

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Investigation of 5HT2AR using super resolution microscopy

The 5-HT2A serotonin receptor is important for mediating serotonin’s actions on regulating cognition, perception, and affect. In some psychotic disorders like Parkinson’s Psychosis, 5-HT2A antagonists are the treatment of choice. Psychedelic drugs mediate their actions via 5-HT2A agonism and it is possible that their beneficial actions could also be mediated by 5-HT2A receptors. While psychedelics have shown promising results, the exact mechanisms by which this occurs is yet to be elucidated. One notable byproduct of psychedelic administration is enhanced spinogenesis, the growth of dendritic spines, which fosters new synaptic connections in cortical neurons. At the synapse, transmembrane proteins cluster in nanocolumns, including PDZ proteins known to interact with 5-HT2A receptors, that work together to facilitate neuronal communication. Interestingly, the number of nanodomains correlates positively with synaptic strength, suggesting a pivotal but not yet understood role for 5-HT2A receptors in synaptic plasticity. Here I am using advanced super-resolution and, ultimately, single molecule studies to understand the role of synaptic 5-HT2A receptors in psychedelic drug actions. Using newly created transgenic mice and sparse virally mediated transduction we have found 5-HT2A receptors enriched in spines of cortical pyramidal neurons. These results imply that the effects of psychedelics may be mediated directly at dendritic spines to enhance plasticity.