REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis
- Washington University School of Medicine in St. Louis, United States
- Saint Louis University School of Medicine, United States
Abstract
The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBa, and deletion of REV-ERBa causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBa deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBa axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.
Data availability
The microarray data used in Fig. 1 is available on ArrayExpress E-MTAB-7590 and E-MTAB-7151.We have also uploaded all of the raw data from all of the figures in the paper as Source Files and to Dryad, which is available at: https://doi.org/10.5061/dryad.nzs7h44p1.This includes all of the image quantification data. Raw image files were not uploaded, as there are several hundred and they exceed 20GB.
-
REV-ERBα mediates complement expression and circadian regulation of microglial synaptic phagocytosisDryad Digital Repository, doi:10.5061/dryad.nzs7h44p1.
Article and author information
Author details
Erik Steven Musiek
Funding
National Institute on Aging (R01AG054517)
- Erik Steven Musiek
National Institute on Aging (R01AG063743)
- Erik Steven Musiek
Cure Alzheimer's Fund (Investigator award)
- Erik Steven Musiek
Coins for Alzheimer's Research Trust (Investigator award)
- Erik Steven Musiek
National Science Foundation (DGE- 1745038)
- Percy Griffin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, and were approved by the institutional animal care and use committee (IACUC) at Washington University under protocol 2017-0124 (E. Musiek, PI).
Copyright
© 2020, Griffin 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.
Metrics
-
- 2,649
- views
-
- 429
- downloads
-
- 49
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis
eLife 9:e58765.
https://doi.org/10.7554/eLife.58765
Further reading
-
- Neuroscience
Time estimation is an essential prerequisite underlying various cognitive functions. Previous studies identified ‘sequential firing’ and ‘activity ramps’ as the primary neuron activity patterns in the medial frontal cortex (mPFC) that could convey information regarding time. However, the relationship between these patterns and the timing behavior has not been fully understood. In this study, we utilized in vivo calcium imaging of mPFC in rats performing a timing task. We observed cells that showed selective activation at trial start, end, or during the timing interval. By aligning long-term time-lapse datasets, we discovered that sequential patterns of time coding were stable over weeks, while cells coding for trial start or end showed constant dynamism. Furthermore, with a novel behavior design that allowed the animal to determine individual trial interval, we were able to demonstrate that real-time adjustment in the sequence procession speed closely tracked the trial-to-trial interval variations. And errors in the rats’ timing behavior can be primarily attributed to the premature ending of the time sequence. Together, our data suggest that sequential activity maybe a stable neural substrate that represents time under physiological conditions. Furthermore, our results imply the existence of a unique cell type in the mPFC that participates in the time-related sequences. Future characterization of this cell type could provide important insights in the neural mechanism of timing and related cognitive functions.
-
- Neuroscience
Granule cells of the cerebellum make up to 175,000 excitatory synapses on a single Purkinje cell, encoding the wide variety of information from the mossy fibre inputs into the cerebellar cortex. The granule cell axon is made of an ascending portion and a long parallel fibre extending at right angles, an architecture suggesting that synapses formed by the two segments of the axon could encode different information. There are controversial indications that ascending axon (AA) and parallel fibre (PF) synapse properties and modalities of plasticity are different. We tested the hypothesis that AA and PF synapses encode different information, and that the association of these distinct inputs to Purkinje cells might be relevant to the circuit and trigger plasticity, similar to the coincident activation of PF and climbing fibre inputs. Here, by recording synaptic currents in Purkinje cells from either proximal or distal granule cells (mostly AA and PF synapses, respectively), we describe a new form of associative plasticity between these two distinct granule cell inputs. We show for the first time that synchronous AA and PF repetitive train stimulation, with inhibition intact, triggers long-term potentiation (LTP) at AA synapses specifically. Furthermore, the timing of the presentation of the two inputs controls the outcome of plasticity and induction requires NMDAR and mGluR1 activation. The long length of the PFs allows us to preferentially activate the two inputs independently, and despite a lack of morphological reconstruction of the connections, these observations reinforce the suggestion that AA and PF synapses have different coding capabilities and plasticity that is associative, enabling effective association of information transmitted via granule cells.
