Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Author:

Sardar Debosmita12ORCID,Cheng Yi-Ting123ORCID,Woo Junsung12,Choi Dong-Joo12ORCID,Lee Zhung-Fu124ORCID,Kwon Wookbong12ORCID,Chen Hsiao-Chi125ORCID,Lozzi Brittney126ORCID,Cervantes Alexis12,Rajendran Kavitha12ORCID,Huang Teng-Wei1ORCID,Jain Antrix7ORCID,Arenkiel Benjamin R.389ORCID,Maze Ian101112ORCID,Deneen Benjamin123413ORCID

Affiliation:

1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.

2. Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA.

3. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.

4. Program in Development, Disease Models, and Therapeutics, Baylor College of Medicine, Houston, TX, USA.

5. The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX, USA.

6. Genetics and Genomics Graduate Program, Baylor College of Medicine, Houston, TX, USA.

7. Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX, USA.

8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

9. Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA.

10. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

11. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

12. Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

13. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.

Abstract

Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional up-regulation and down-regulation in astrocytes, highlighted by the identification of Slc22a3 as an activity-inducible astrocyte gene that encodes neuromodulator transporter Slc22a3 and regulates sensory processing in the mouse olfactory bulb. Loss of astrocytic Slc22a3 reduced serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduced the expression of γ-aminobutyric acid (GABA) biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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