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Neurobiol Dis. 2017 Dec;108:128-139. doi: 10.1016/j.nbd.2017.08.007. Epub 2017 Aug 18.

Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition.

Author information

1
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address: maltese@med.uniroma2.it.
2
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy. Electronic address: martella@med.uniroma2.it.
3
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address: paola.imbriani@gmail.com.
4
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium.
5
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, 3000 Leuven, Belgium. Electronic address: karolien.billion@kuleuven.vib.be.
6
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy. Electronic address: giuseppe.sciamanna@uniroma2.it.
7
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy. Electronic address: g.ponterio@hsantalucia.it.
8
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy. Electronic address: a.tassone@hsantalucia.it.
9
Fondazione Don Gnocchi, Milan, Italy. Electronic address: msantoro@dongnocchi.it.
10
Fondazione Santa Lucia IRCCS, Rome, Italy. Electronic address: p.bonsi@hsantalucia.it.
11
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy. Electronic address: pisani@uniroma2.it.
12
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, 3000 Leuven, Belgium. Electronic address: rose.goodchild@kuleuven.vib.be.

Abstract

Striatal dysfunction is implicated in many movement disorders. However, the precise nature of defects often remains uncharacterized, which hinders therapy development. Here we examined striatal function in a mouse model of the incurable movement disorder, myoclonus dystonia, caused by SGCE mutations. Using RNAseq we found surprisingly normal gene expression, including normal levels of neuronal subclass markers to strongly suggest that striatal microcircuitry is spared by the disease insult. We then functionally characterized Sgce mutant medium spiny projection neurons (MSNs) and cholinergic interneurons (ChIs). This revealed normal intrinsic electrophysiological properties and normal responses to basic excitatory and inhibitory neurotransmission. Nevertheless, high-frequency stimulation in Sgce mutants failed to induce normal long-term depression (LTD) at corticostriatal glutamatergic synapses. We also found that pharmacological manipulation of MSNs by inhibiting adenosine 2A receptors (A2AR) restores LTD, again pointing to structurally intact striatal circuitry. The fact that Sgce loss specifically inhibits LTD implicates this neurophysiological defect in myoclonus dystonia, and emphasizes that neurophysiological changes can occur in the absence of broad striatal dysfunction. Further, the positive effect of A2AR antagonists indicates that this drug class be tested in DYT11/SGCE dystonia.

KEYWORDS:

Adenosine 2A receptor; Dystonia; Plasticity; Sarcoglycan; Striatum

PMID:
28823931
DOI:
10.1016/j.nbd.2017.08.007
[Indexed for MEDLINE]

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