Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: Role of endogenous acetylcholine

Giuseppina Martella, Annalisa Tassone, Giuseppe Sciamanna, Paola Platania, Dario Cuomo, Maria Teresa Viscomi, Paola Bonsi, Emanuele Cacci, Stefano Biagioni, Alessandro Usiello, Giorgio Bernardi, Nutan Sharma, David G. Standaert, Antonio Pisani

Research output: Contribution to journalArticle

Abstract

DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been documented. The loss of LTD and SD on one hand, and the increase in LTP on the other, demonstrate that a 'loss of inhibition' characterizes the impairment of synaptic plasticity in this model of DYT1 dystonia. More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia.

Original languageEnglish
Pages (from-to)2336-2349
Number of pages14
JournalBrain
Volume132
Issue number9
DOIs
Publication statusPublished - Sep 2009

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Neuronal Plasticity
Dystonia
Long-Term Synaptic Depression
Acetylcholine
Corpus Striatum
Long-Term Potentiation
Cholinergic Antagonists
Cholinergic Agents
Muscarinic M4 Receptors
Muscarinic M2 Receptors
Muscarinic M1 Receptors
Depression
Aptitude
Penetrance
Dyskinesias
Acetylcholinesterase
Posture
Knockout Mice
Synapses
Transgenic Mice

Keywords

  • Acetylcholine
  • Dystonia
  • Electrophysiology
  • Striatum
  • Synaptic plasticity

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia : Role of endogenous acetylcholine. / Martella, Giuseppina; Tassone, Annalisa; Sciamanna, Giuseppe; Platania, Paola; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Cacci, Emanuele; Biagioni, Stefano; Usiello, Alessandro; Bernardi, Giorgio; Sharma, Nutan; Standaert, David G.; Pisani, Antonio.

In: Brain, Vol. 132, No. 9, 09.2009, p. 2336-2349.

Research output: Contribution to journalArticle

Martella, G, Tassone, A, Sciamanna, G, Platania, P, Cuomo, D, Viscomi, MT, Bonsi, P, Cacci, E, Biagioni, S, Usiello, A, Bernardi, G, Sharma, N, Standaert, DG & Pisani, A 2009, 'Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: Role of endogenous acetylcholine', Brain, vol. 132, no. 9, pp. 2336-2349. https://doi.org/10.1093/brain/awp194
Martella, Giuseppina ; Tassone, Annalisa ; Sciamanna, Giuseppe ; Platania, Paola ; Cuomo, Dario ; Viscomi, Maria Teresa ; Bonsi, Paola ; Cacci, Emanuele ; Biagioni, Stefano ; Usiello, Alessandro ; Bernardi, Giorgio ; Sharma, Nutan ; Standaert, David G. ; Pisani, Antonio. / Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia : Role of endogenous acetylcholine. In: Brain. 2009 ; Vol. 132, No. 9. pp. 2336-2349.
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abstract = "DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been documented. The loss of LTD and SD on one hand, and the increase in LTP on the other, demonstrate that a 'loss of inhibition' characterizes the impairment of synaptic plasticity in this model of DYT1 dystonia. More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia.",
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AU - Platania, Paola

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AU - Bonsi, Paola

AU - Cacci, Emanuele

AU - Biagioni, Stefano

AU - Usiello, Alessandro

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