# A humanized Gs-coupled DREADD for circuit and behavior modulation

## TL;DR

Scientists developed a humanized version of a DREADD receptor that can safely and effectively modulate brain circuits and improve Parkinson's symptoms in mice.

## Contribution

A fully humanized Gs-coupled DREADD (hM3Ds) was developed and shown to be effective in a Parkinson's disease model.

## Key findings

- hM3Ds has a comparable ligand response profile to the original rM3Ds DREADD.
- hM3Ds activated D1-MSNs and improved Parkinsonian symptoms in a mouse model.
- The humanized DREADD is likely safer and suitable for clinical translation.

## 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.