Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits
- King's College London, United Kingdom
Abstract
The assembly of specific neuronal circuits relies on the expression of complementary molecular programs in presynaptic and postsynaptic neurons. In the cerebral cortex, the tyrosine kinase receptor ErbB4 is critical for the wiring of specific populations of GABAergic interneurons, in which it paradoxically regulates both the formation of inhibitory synapses as well as the development of excitatory synapses received by these cells. Here we found that Nrg1 and Nrg3, two members of the neuregulin family of trophic factors, respectively regulate the inhibitory outputs and excitatory inputs of interneurons in the mouse cerebral cortex. The differential role of Nrg1 and Nrg3 in this process is not due to their receptor-binding EGF-like domain, but rather to their distinctive subcellular localization within pyramidal cells. Our study reveals a novel strategy for the assembly of cortical circuits that involves the differential subcellular sorting of family-related synaptic proteins.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for the figures and figure supplements.
Article and author information
Author details
David Exposito-Alonso
Sandra Pascual-García
Funding
Medical Research Council (MR/S010785/1)
- Oscar Marín
- Beatriz Rico
Innovative Medicines Initiative (AIMS-2-TRIALS,777394)
- Oscar Marín
- Beatriz Rico
Fondation Roger de Spoelberch
- Oscar Marín
La caixa Foundation
- David Exposito-Alonso
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Nils Brose, Max Planck Institute of Experimental Medicine, Germany
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals in accordance with European regulations, and Home Office personal and project licenses (PPL 0808-2004-2019, PPL PD025E9BC-2019-2024) under the UK Animals (Scientific Procedures) 1986 Act. The experiments performed in this study, have been designed to follow the 3R's rules whenever possible.
Version history
- Received: March 17, 2020
- Accepted: December 14, 2020
- Accepted Manuscript published: December 15, 2020 (version 1)
- Version of Record published: December 22, 2020 (version 2)
Copyright
© 2020, Exposito-Alonso 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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Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits
eLife 9:e57000.
https://doi.org/10.7554/eLife.57000
Further reading
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Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are often assumed to feed pools that are mobilized more quickly, in a series. However, electrophysiological studies of synaptic transmission have suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool. Here, we use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses and a parallel organization that prevents intermixing between the pools, even when stimulation is intense enough to drive exocytosis at the maximum rate. The experiments additionally demonstrate extensive heterogeneity among synapses in the relative sizes of the slowly and quickly mobilized reserve pools, which suggests equivalent heterogeneity in the numbers of reluctant and fast-releasing readily releasable vesicles that may be relevant for understanding information processing and storage.
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