A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules
A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABA<sub>A</sub> potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABA<sub>A</sub> receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules' nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.
Authors
- Douglas Myers-Turnbull (ORCID: https://orcid.org/0000-0003-3610-4808)
- Jung Ho Gong (ORCID: https://orcid.org/0000-0003-0382-8279)
- Matthew N. McCarroll (ORCID: https://orcid.org/0000-0001-7080-3210)
- Jack C. Taylor (ORCID: https://orcid.org/0000-0002-6431-9956)
- Lain X. Pierce (ORCID: https://orcid.org/0000-0002-4656-6275)
- Jason K. Sello (ORCID: https://orcid.org/0000-0001-6263-7902)
- Ryan Hibbs (ORCID: https://orcid.org/0000-0003-4283-1147)
- David Kokel (ORCID: https://orcid.org/0000-0002-1981-1511)
- Elizabeth Sisko
- Grant Burley
- D. M. Young
- Jinfeng Teng
Institutions
- University of California, San Francisco (US)
- Brown University (US)
- University of California San Diego (US)
- University Memory and Aging Center (US)
- Institute for Neurodegenerative Disorders (US)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2024-09-17
- DOI
- https://doi.org/10.1021/acschemneuro.4c00426
- Citations
- 2
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.54
Funders
- Silicon Valley Community Foundation
- Paul G. Allen Family Foundation
- Chan Zuckerberg Initiative
- National Institutes of Health
- University of California, San Diego
- University of California, San Francisco
- National Institute on Alcohol Abuse and Alcoholism
- Weill Institute for Neurosciences, University of California, San Francisco
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases