Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia

G. Martella, M. Maltese, R. Nisticò, T. Schirinzi, G. Madeo, G. Sciamanna, G. Ponterio, A. Tassone, G. Mandolesi, V. Vanni, M. Pignatelli, P. Bonsi, A. Pisani

Research output: Contribution to journalArticle

Abstract

DYT1 dystonia is a movement disorder caused by a deletion in the C-terminal of the protein torsinA. It is unclear how torsinA mutation might disrupt cellular processes encoding motor activity, and whether this impairment occurs in specific brain regions. Here, we report a selective impairment of corticostriatal synaptic plasticity in knock-in mice heterozygous for δ-torsinA (Tor1a+/δgag mice) as compared to controls (Tor1a+/+ mice). In striatal spiny neurons from Tor1a+/δgag mice, high-frequency stimulation failed to induce long-term depression (LTD), whereas long-term potentiation (LTP) exhibited increased amplitude. Of interest, blockade of D2 dopamine receptors (D2Rs) increased LTP in Tor1a+/+ mice to a level comparable to that measured in Tor1a+/δgag mice and normalized the levels of potentiation across mouse groups. A low-frequency stimulation (LFS) protocol was unable to depotentiate corticostriatal synapses in Tor1a+/δgag mice. Muscarinic M1 acetylcholine receptor (mAChR) blockade rescued plasticity deficits. Additionally, we found an abnormal responsiveness of cholinergic interneurons to D2R activation, consisting in an excitatory response rather than the expected inhibition, further confirming an imbalance between dopaminergic and cholinergic signaling in the striatum. Conversely, synaptic activity and plasticity in the CA1 hippocampal region were unaltered in Tor1a+/δgag mice. Importantly, the M1 mAChR-dependent enhancement of hippocampal LTP was unaffected in both genotypes. Similarly, both basic properties of dopaminergic nigral neurons and their responses to D2R activation were normal.These results provide evidence for a regional specificity of the electrophysiological abnormalities observed and demonstrate the reproducibility of such alterations in distinct models of DYT1 dystonia.

Original languageEnglish
Pages (from-to)124-132
Number of pages9
JournalNeurobiology of Disease
Volume65
DOIs
Publication statusPublished - May 2014

Fingerprint

Neuronal Plasticity
Dystonia
Long-Term Potentiation
Cholinergic Agents
Muscarinic M1 Receptors
Hippocampal CA1 Region
Corpus Striatum
Dopamine D2 Receptors
Dopaminergic Neurons
Movement Disorders
Cholinergic Receptors
Muscarinic Receptors
Interneurons
Substantia Nigra
Protein C
Synapses
Motor Activity
Genotype
Depression
Neurons

Keywords

  • Cholinergic interneurons
  • D2 dopamine receptor
  • Dystonia
  • Long-term depression
  • Long-term potentiation
  • Muscarinic receptor antagonists
  • Striatum

ASJC Scopus subject areas

  • Neurology

Cite this

Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia. / Martella, G.; Maltese, M.; Nisticò, R.; Schirinzi, T.; Madeo, G.; Sciamanna, G.; Ponterio, G.; Tassone, A.; Mandolesi, G.; Vanni, V.; Pignatelli, M.; Bonsi, P.; Pisani, A.

In: Neurobiology of Disease, Vol. 65, 05.2014, p. 124-132.

Research output: Contribution to journalArticle

Martella, G, Maltese, M, Nisticò, R, Schirinzi, T, Madeo, G, Sciamanna, G, Ponterio, G, Tassone, A, Mandolesi, G, Vanni, V, Pignatelli, M, Bonsi, P & Pisani, A 2014, 'Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia', Neurobiology of Disease, vol. 65, pp. 124-132. https://doi.org/10.1016/j.nbd.2014.01.016
Martella, G. ; Maltese, M. ; Nisticò, R. ; Schirinzi, T. ; Madeo, G. ; Sciamanna, G. ; Ponterio, G. ; Tassone, A. ; Mandolesi, G. ; Vanni, V. ; Pignatelli, M. ; Bonsi, P. ; Pisani, A. / Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia. In: Neurobiology of Disease. 2014 ; Vol. 65. pp. 124-132.
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