Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum

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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.

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Marta Maltese

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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Jennifer Stanic

Department of Pharmacology, University of Milan, Milan, Italy

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Annalisa Tassone

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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Giuseppe Sciamanna

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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Giulia Ponterio

Lab Neurophysiology and Plasticity, Fondazione Santa Lucia IRCCS, Rome, Italy

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Valentina Vanni

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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Giuseppina Martella

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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Paola Imbriani

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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"This ORCID iD identifies the author of this article:" 0000-0003-3373-5073
Paola Bonsi

Lab Neurophysiology and Plasticity, Fondazione Santa Lucia IRCCS, Rome, Italy

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5940-9028
Nicola Biagio Mercuri

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

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Fabrizio Gardoni

Department of Pharmacology, University of Milan, Milan, Italy

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Antonio Pisani

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

For correspondence
pisani@uniroma2.it

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8432-594X

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

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.