Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice
- University College Cork, Ireland
Abstract
Social behaviour is regulated by activity of host-associated microbiota across multiple species. However, the molecular mechanisms mediating this relationship remain elusive. We therefore determined the dynamic, stimulus-dependent transcriptional regulation of germ-free (GF) and GF mice colonised post weaning (exGF) in the amygdala, a brain region critically involved in regulating social interaction. In GF mice the dynamic response seen in controls was attenuated and replaced by a marked increase in expression of splicing factors and alternative exon usage in GF mice upon stimulation, which was even more pronounced in exGF mice. In conclusion, we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions. Our findings may help toward understanding neurodevelopmental events leading to social behaviour dysregulation, such as those found in autism spectrum disorders (ASDs).
Data availability
The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus [86] and are accessible through GEO Series accession number GSE114702 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE114702
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Data from: Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE114702).
Article and author information
Author details
Funding
Science Foundation Ireland (12/RC/2273)
- Fergus Shanahan
- Gerard Clarke
- Marcus J Claesson
- Timothy G Dinan
- John F Cryan
Irish Research Council (GOIPD/2014/355)
- Roman M Stilling
- John F Cryan
Irish Health Board
- Timothy G Dinan
- John F Cryan
NARSAD (20771)
- Gerard Clarke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations provided by Laboratory Animal Science and Training (LAST) Ireland. All of the animals were handled according to institutional protocols approved by the Animal Ethics Experimentation Committee (AEEC) of University College Cork (#2015/014) and the Health Products Regulatory Authority (HPRA) Ireland (#AE19130/P023). Every effort was made to minimize suffering and animals were killed humanely.
Copyright
© 2018, Stilling 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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Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice
eLife 7:e33070.
https://doi.org/10.7554/eLife.33070
Further reading
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Mice raised in sterile environments are less social.
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- Neuroscience
The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.
