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Updated: May 10, 2025

Assaying Circuit Specific Regulation of Adult Hippocampal Neural Precursor Cells
Published on: July 24, 2019
A humanized Gs-coupled DREADD for circuit and behavior modulation
Qi Zhang1, Ruiqi Wang2, Liang Zhang3
1Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
Abstract:
Designer receptors exclusively activated by designer drugs (DREADDs) play important roles in neuroscience research and show great promise for future clinical interventions in neurological diseases. The Gs-coupled DREADD, rM3Ds, modulates excitability in neuron subsets that are sensitive to downstream effectors of Gs protein. However, given the non-human nature of the rM3Ds backbone, risks about potential immunogenicity and tolerability exist when considering clinical translation. Here, we report the development of a whole sequence-humanized Gs-coupled DREADD, hM3Ds. We found that hM3Ds has a comparable DREADD ligand response profile to rM3Ds. We then selectively expressed hM3Ds in D1 medium spiny neurons (D1-MSNs) and found that hM3Ds was able to activate the D1-MSNs-mediated basal ganglia direct pathway and alleviate Parkinsonian phenotypes in a Parkinson's disease mouse model. In conclusion, this engineered humanized Gs-coupled DREADD is suitable as an effective, and likely safer, DREADD tool for both research and future clinical applications.
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