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.