Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior
- Icahn School of Medicine at Mount Sinai, United States
- Icahn School of Medicine at Mount Sinaii, United States
- BERG, United States
- Virginia Commonwealth University, United States
Abstract
Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of saline in non-obese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.
Article and author information
Author details
Reviewing Editor
- Peggy Mason, University of Chicago, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Icahn School of Medicine at Mount Sinai (#08-0676, #08-0675; LA10-00398; LA12-00193; LA12-00146).
Version history
- Received: December 3, 2015
- Accepted: April 7, 2016
- Accepted Manuscript published: April 20, 2016 (version 1)
- Accepted Manuscript updated: May 3, 2016 (version 2)
- Version of Record published: May 16, 2016 (version 3)
Copyright
© 2016, Gacias et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior
eLife 5:e13442.
https://doi.org/10.7554/eLife.13442
Further reading
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Microbes in the gut influence the social behaviour of mice.
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Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
