Astrocyte processing of serotonin regulates olfactory perception

Researchers at Baylor College of Medicine and collaborating institutions report in the journal Science the responses of astrocytes to olfactory stimulation, revealing a new mechanism that is required to maintain astrocyte-neuron communication and process olfactory sensation.

"Previous studies have shown that under natural conditions in a living animal, olfactory stimulation of the brain activates neurons first, which changes the genes these neurons express to be able to mediate the olfactory sensation," said first author Dr. Debosmita Sardar, a postdoctoral associate in Dr. Benjamin Deneen's lab at Baylor. "In this study, we investigated what occurred to astrocytes following neural activity during olfactory stimulation and uncovered changes that had not been described before."

Olfactory stimulation triggered an increase of serotonin transporter Slc22a3 on the astrocytes, which mediated serotonin transport into the cells. "We followed serotonin inside the astrocytes and were surprised to discover that it traveled to the cell nucleus, where it bound to histones, proteins attached to the DNA that help regulate astrocyte gene expression," Sardar said. "Serotonin bound to DNA acted as a switch, which controlled gene expression."

Interestingly, serotonin regulates the expression of astrocyte genes involved in the production of the neurotransmitter GABA, which then feeds back to neurons regulating the neural circuit fundamental to sensory perception.

"We showed that losing transporter Slc22a3 in astrocytes reduced serotonin levels in the cells and led to alterations in serotonin-bound DNA," Sardar said. "In turn, this reduced the expression of genes involved in the synthesis of GABA and decreased astrocytic GABA release, which disturbed the neural circuits of olfactory sensation."

Serotonin is well known for its contribution to normal brain function as well as being involved in addiction and depression. "Here we discovered a new function of serotonin in astrocytes. Serotonin triggers changes in astrocyte gene expression patterns, turning astrocytes into a hub of olfactory sensation processing," Sardar said.

"This project has uncovered novel aspects of astrocyte function," said Deneen, professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery and director of the Center for Cancer Neuroscience at Baylor. He also is the corresponding author of the work. "We are learning that astrocytes are very plastic, just as neurons are, meaning that astrocytes can change their characteristics and functions in response to environmental stimuli. They listen to neurons and respond, and their two-way communication is at the core of sensory processing and ultimately, animal behavior."

Other contributors to this work include Yi-Ting Cheng, Junsung Woo, Dong-Joo Choi, Zhung-Fu Lee, Wookbong Kwon, Hsiao-Chi Chen, Brittney Lozzi, Alexis Cervantes, Kavitha Rajendran, Teng-Wei Huang, Antrix Jain, Benjamin Arenkiel and Ian Maze. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Icahn School of Medicine at Mount Sinai.

This work was supported by grants from the NIH (NINDS R01-NS071153, R01-AG071687, NIMH R01-MH116900, NIDCD 1K99-DC019668). Further support was provided by Dan L Duncan Comprehensive Cancer Center NIH award (P30 CA125123), CPRIT Core Facility Award (RP210227), NIH High End Instrument award (S10OD026804) and National Institutes of Health Cancer Center Grant (P30 CA125123).