09:02pm Monday 20 January 2020

New Biosensors Reveal Workings of Anti-Psychotic Drugs in the Living Brain


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A clump of cells that are designed to change color when they detect a specific neural message nestle near a blood vessel in the brain. (Credit: David Kleinfeld Lab)

Although delusions and hallucinations characterize the illness, people with schizophrenia also struggle to sustain attention or recall information in a particular order, difficulties that interfere with their ability to hold a job or function well.

Drugs that belong to a class called atypical neuroleptics have become the most commonly prescribed treatment for schizophrenia, in part for their ability to improve these cognitive functions. How they altered brain chemisty was uncertain, however. Atypical neuroleptics elicit large releases of the neurotransmitter acetylcholine. But they had also been shown to barricade a particular type of receptor on the surface of cultured cells grown in a dish, which could block the message.

The question was, which action prevails in the brain? The answer might guide the development of more effective drugs with fewer side effects. “The hunt is now on,” said Lee Schroeder, a student in the medical scientist training program who shares lead authorship on the paper. “What about these drugs helps? That’s where our cells come in.”

To find out, the team designed biological cells that change color when acetylcholine latches onto this particular class of receptors, called M1. That allowed them to see when M1 receptors received the chemical message, an event neuroscientists had previously been unable to detect in a living, intact brain. “It’s a world of signaling between cells that we were blind to before,” said David Kleinfeld, professor of physics and member of UC San Diego’s Center for Neural Circuits and Behavior, who led the collaboration that invented the system.

The team implanted the cells, which they call CNiFERs (pronounced “sniffers”), in rat brains, then stimulated a deeper part of the brain in a way known to release acetylcholine nearby. They saw a color change, evidence that the CNiFERs were working. Then they gave the rats one of two atypical neuroleptics. In both cases, the drug severely depressed the response, indicating that the receptor-blocking action overrides the increase in acetylcholine, the authors report online in Nature Neuroscience December 13.

CNiFERs could be re-designed to detect the activity of other types of receptors as well, work that is underway. “The technique puts CNiFERs together from easily obtained molecular components,” said Quoc-Thang Nguyen, a former research scientist in Kleinfeld’s lab who shares lead authorship with Schroeder. Nguyen recently founded Femtoscience, a company that has licensed the technology from UC San Diego and will develop it as a way to screen drugs that could treat diseases of the brain.

Other co-authors include Marco Mank, Arnaud Muller, Palmer Taylor, and Oliver Griesbeck. The National Institutes on Biomedical Imaging and Bioengineering, Drug Abuse, and Mental Health funded this work.

Media Contact: Kim McDonald, 858-534-7572 or scinews@ucsd.edu

Contact: David Kleinfeld, dk@physics.ucsd.edu

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