A suite of engineered mice for interrogating psychedelic drug actions
Yi-Ting Chiu, Wei Wang, Pierre Llorach, Kasey Bowyer, Bei Liu, Noah Sciaky, Kunjie Hua, Chongguang Chen, Grégory Scherrer, Zhuhao Wu, Ariel Y. Deutch, Gavin P. Schmitz, Karen Huang, D. Dewran Koçak, Sarah L. Mott, Jesse K. Niehaus, Jeffrey F. Diberto, Justin G. English, Jessica J. Walsh, Melissa A. Herman, William C. Wetsel, Bryan L. Roth
bioRxiv (Cold Spring Harbor Laboratory) September 26, 2023 preprint DOI: 10.1101/2023.09.25.559347 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Methodological development and validation study |
|---|---|
| Population | Engineered mice (Htr2a-EGFP-CT-IRES-CreERT2, humanized Htr2a, and constitutive Htr2A-Cre lines) |
| Interventions | Lysergic acid diethylamide (LSD) psilocybin |
| Keywords | Suite Drug Pharmacology |
| Citations | 15 |
| Key points | Newly engineered mouse lines enable detailed mapping of HTR2A-expressing neurons and demonstrate expected behavioral and electrophysiological responses to psychedelic drugs, validating their use for studying psychedelic drug actions in vivo. |
Abstract
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 .