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Brain Advance Access originally published online on July 29, 2009
Brain 2009 132(9):2336-2349; doi:10.1093/brain/awp194
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Giuseppina Martella1,*, Annalisa Tassone2,*, Giuseppe Sciamanna2, Paola Platania1, Dario Cuomo2, Maria Teresa Viscomi2, Paola Bonsi2, Emanuele Cacci3,4, Stefano Biagioni3,4, Alessandro Usiello5,6, Giorgio Bernardi1,2, Nutan Sharma7, David G. Standaert8 and Antonio Pisani1,2

1 Department of Neuroscience, University "Tor Vergata", 00133 Rome, Italy 2 Fondazione Santa Lucia I.R.C.C.S., Rome, Italy 3 Department of Cell and Developmental Biology, Neurobiology Research Unit, University "La Sapienza", Rome, Italy 4 "Daniel Bovet" Neurobiology Research Center, University "La Sapienza", Rome, Italy 5 CEINGE Biotecnologie Avanzate, Naples, Italy 6 Department of Health Sciences, University of Molise, Italy 7 Massachusetts General Hospital, Harvard Medical School, Boston, USA 8 University of Alabama at Birmingham, Birmingham, USA

Correspondence to: Antonio Pisani, MD, Department of Neuroscience, University "Tor Vergata", 00133 Rome, Italy E-mail: pisani{at}uniroma2.it

Correspondence may also be addressed to: David G. Standaert, MD, PhD, University of Alabama at Birmingham, Birmingham, USA E-mail: dstandaert{at}uab.edu

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.

Key Words: dystonia; synaptic plasticity; striatum; acetylcholine; electrophysiology

Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; HFS, high-frequency stimulation; hMT, mutant human torsinA; hWT, normal human torsinA; LFS, low-frequency stimulation; LTD, long-term depression; LTP, long-term potentiation; MSN, medium spiny neuron; NT, non-transgenic; PPR, paired-pulse ratio; SD, synaptic depotentiation; RMP, resting membrane potential

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Received February 24, 2009. Revised May 6, 2009. Accepted June 15, 2009.

*These authors contributed equally to this work.


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