Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum
- University of Rome Tor Vergata, Italy
- University of Milan, Italy
- Fondazione Santa Lucia IRCCS, Italy
Abstract
The onset of abnormal movements in DYT1 dystonia is between childhood and adolescence, though it is unclear why clinical manifestations appear during this developmental period. Plasticity at corticostriatal synapses is critically involved in motor memory. In the Tor1a+/Δgag DYT1 dystonia mouse model, long-term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded. Analysis of dendritic spines showed an increase of both spine width and mature mushroom spines in Tor1a+/Δgag neurons, paralleled by an enhanced AMPA receptor (AMPAR) accumulation. BDNF regulates AMPAR expression during development. Accordingly, both proBDNF and BDNF levels were significantly higher in Tor1a+/Δgag mice. Consistently, antagonism of BDNF rescued synaptic plasticity deficits and AMPA currents. Our findings demonstrate that early loss of functional and structural synaptic homeostasis represents a unique endophenotypic trait during striatal maturation, promoting the appearance of clinical manifestations in mutation carriers.
Article and author information
Author details
Funding
Ministero dell'Istruzione, dell'Università e della Ricerca (PRIN 2010-2011)
- Antonio Pisani
Ministero dell'Istruzione, dell'Università e della Ricerca (PRIN 2010-2011)
- Fabrizio Gardoni
Dystonia Medical Research Foundation (2017)
- Antonio Pisani
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal breeding and handling were performed in accordance with the guidelines for the use of animals in biomedical research provided by the European Union's directives and Italian laws (2010/63EU, D.lgs. 26/2014; 406 86/609/CEE, D.Lgs 116/1992). The experimental procedures were approved by Fondazione Santa Lucia and University Tor Vergata Animal Care and Use Committees and the Italian Ministry of Health (authorization #223/2017-PR).
Copyright
© 2018, Maltese 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
-
- 1,793
- views
-
- 313
- downloads
-
- 63
- 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)
Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum
eLife 7:e33331.
https://doi.org/10.7554/eLife.33331
Further reading
-
- Neuroscience
In albino mice and EphB1 knockout mice, mistargeted retinal ganglion cell axons form dense islands of axon terminals in the dorsal lateral geniculate nuclei (dLGN). The formation of these islands of retinal input depends on developmental patterns of spontaneous retinal activity. We reconstructed the microcircuitry of the activity-dependent islands and found that the boundaries of the island represent a remarkably strong segregation within retinogeniculate connectivity. We conclude that when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit within the otherwise fully connected network. The fact that there is a developmental starting condition that can induce a synaptically segregated microcircuit has important implications for our understanding of the organization of visual circuits and our understanding of the implementation of activity-dependent development.
-
- Neuroscience
The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed, we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.
