Evidence in Primates Supporting the Use of Chemogenetics for the Treatment of Human Refractory Neuropsychiatric Disorders

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2021 Apr 25

PMID 33895327

Citations 20

Authors

Patrick H Roseboom

Sascha A L Mueller

Jonathan A Oler

Andrew S Fox

Marissa K Riedel

Victoria R Elam

Miles E Olsen

Juan L Gomez

Matthew A Boehm

Alexandra H DiFilippo

Bradley T Christian

Michael Michaelides

Ned H Kalin

Affiliations

Soon will be listed here.

Abstract

Non-human primate (NHP) models are essential for developing and translating new treatments that target neural circuit dysfunction underlying human psychopathology. As a proof-of-concept for treating neuropsychiatric disorders, we used a NHP model of pathological anxiety to investigate the feasibility of decreasing anxiety by chemogenetically (DREADDs [designer receptors exclusively activated by designer drugs]) reducing amygdala neuronal activity. Intraoperative MRI surgery was used to infect dorsal amygdala neurons with AAV5-hSyn-HA-hM4Di in young rhesus monkeys. In vivo microPET studies with [C]-deschloroclozapine and postmortem autoradiography with [H]-clozapine demonstrated selective hM4Di binding in the amygdala, and neuronal expression of hM4Di was confirmed with immunohistochemistry. Additionally, because of its high affinity for DREADDs, and its approved use in humans, we developed an individualized, low-dose clozapine administration strategy to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in hM4Di-expressing monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology.

Citing Articles

An Honest Reckoning With the Amygdala and Mental Illness.

Fox A, Shackman A Am J Psychiatry. 2024; 181(12):1059-1075.

PMID: 39616453 PMC: 11611071. DOI: 10.1176/appi.ajp.20240941.

Imaging-based chemogenetics for dissecting neural circuits in nonhuman primates.

Minamimoto T, Nagai Y, Oyama K Proc Jpn Acad Ser B Phys Biol Sci. 2024; 100(8):476-489.

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What can neuroimaging of neuromodulation reveal about the basis of circuit therapies for psychiatry?.

Fujimoto S, Fujimoto A, Elorette C, Choi K, Mayberg H, Russ B Neuropsychopharmacology. 2024; 50(1):184-195.

PMID: 39198580 PMC: 11526173. DOI: 10.1038/s41386-024-01976-2.

DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates.

Mueller S, Oler J, Roseboom P, Aggarwal N, Kenwood M, Riedel M Curr Res Neurobiol. 2023; 5:100111.

PMID: 38020807 PMC: 10663133. DOI: 10.1016/j.crneur.2023.100111.

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