A suite of engineered mice for interrogating psychedelic drug actions

Chiu, Y.-t.; Deutch, A.; Wang, W.; Schmitz, G. P.; Huang, K.; Kocak, D.; Lorach, P.; Bowye, K.; Liu, B.; Sciaky, N.; Hua, K.; Chen, C.; Mott, S.; Niehaus, J.; DiBerto, J.; English, J.; Walsh, J.; Scherrer, G.; Herman, M.; Wu, Z.; Wetsel, W. C.; Roth, B. L.

doi:10.1101/2023.09.25.559347

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bioRxiv · 10.1101/2023.09.25.559347

A suite of engineered mice for interrogating psychedelic drug actions

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Abstract

Psychedelic drugs like lysergic acid diethylamide (LSD) and psilocybin have emerged as potentially transformative therapeutics for many neuropsychiatric diseases, including depression, anxiety, post-traumatic stress disorder, migraine, and cluster headaches. LSD and psilocybin exert their psychedelic effects via activation of the 5-hydroxytryptamine 2A receptor (HTR2A). Here we provide a suite of engineered mice useful for clarifying the role of HTR2A and HTR2A-expressing neurons in psychedelic drug actions. We first generated Htr2a-EGFP-CT-IRES-CreERT2 mice (CT:C-terminus) to independently identify both HTR2A-EGFP-CT receptors and HTR2A-containing cells thereby providing a detailed anatomical map of HTR2A and identifying cell types that express HTR2A. We also generated a humanized Htr2a mouse line and an additional constitutive Htr2A-Cre mouse line. Psychedelics induced a variety of known behavioral changes in our mice validating their utility for behavioral studies. Finally, electrophysiology studies revealed that extracellular 5-HT elicited a HTR2A-mediated robust increase in firing of genetically-identified pyramidal neurons--consistent with a plasma membrane localization and mode of action. These mouse lines represent invaluable tools for elucidating the molecular, cellular, pharmacological, physiological, behavioral, and other actions of psychedelic drugs in vivo.

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Chiu, Y.-t., Deutch, A., Wang, W., Schmitz, G. P., Huang, K., Kocak, D., Lorach, P., Bowye, K., Liu, B., Sciaky, N., Hua, K., Chen, C., Mott, S., Niehaus, J., DiBerto, J., English, J., Walsh, J., Scherrer, G., Herman, M., Wu, Z., Wetsel, W. C., Roth, B. L.. 2023-09-26. A suite of engineered mice for interrogating psychedelic drug actions. https://doi.org/10.1101/2023.09.25.559347

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