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

M. Maltese, G. Martella, P. Imbriani, Jeroen Schuermans, Karolien Billion, G. Sciamanna, Febin Farook, G. Ponterio, A. Tassone, M. Santoro, P. Bonsi, A. Pisani, Rose E. Goodchild

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)128-139
Number of pages12
JournalNeurobiology of Disease
Volume108
DOIs
Publication statusPublished - Dec 1 2017

Keywords

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

ASJC Scopus subject areas

  • Neurology

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