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RNA-programmable cell-type monitoring and manipulation in the human cortex with CellREADR
Elizabeth A Matthews1, Jeffrey B Russ2, Yongjun Qian3
1Department of Neurosurgery, Duke University, Durham, NC, USA; Department of Neurobiology, Duke University, Durham, NC, USA.
Cell Reports
|July 23, 2025
Summary
Researchers developed CellREADR, a novel RNA sensing technology, for precise targeting of human neurons. This breakthrough enables better study of neural circuits and potential treatments for brain disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Understanding human neural circuits requires access to diverse cell types.
- Current methods for targeting human neurons are limited, relying on transcriptional enhancers or viral capsids.
Purpose of the Study:
- To demonstrate the utility of CellREADR, a programmable RNA sensor-effector technology, for accessing, monitoring, and manipulating specific human neuron types ex vivo.
- To validate the specificity and reliability of CellREADR for targeting distinct neuronal subpopulations.
Main Methods:
- Development and application of CellREADR technology for RNA sensing and effector protein translation.
- Design of CellREADRs to target calretinin (CALB2) GABAergic interneurons and forkhead box protein P2 (FOXP2) glutamatergic projection neurons.
- Validation of targeting specificity using histological, electrophysiological, and transcriptomic analyses.
Main Results:
- CellREADR demonstrated specific and reliable targeting of CALB2 and FOXP2 neuronal subpopulations in the human cortex ex vivo.
- Expression of channelrhodopsin and GCamp via CellREADR enabled manipulation and monitoring of targeted neurons in live cortical microcircuits.
- Successful validation of CellREADR's programmability and specificity for distinct human neuronal types.
Conclusions:
- CellREADR provides a novel, programmable method for experimental access to specific human neuronal subpopulations.
- This technology holds significant potential for advancing the study of human neural circuits and developing treatments for neurological disorders.
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