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

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.

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

“…Alterations in this tract may affect the regulation of neurotransmitter release in the striatum of these animals (23) and may also relate to the alterations in striatal synaptic plasticity that have recently been observed in a transgenic mouse model with overexpression of the human mutant protein (24). Interestingly, the thalamostriatal tract abnormality failed to reach significance in our earlier study (6) of pathway integrity in human dystonia mutation carriers.…”

Dystonia Pathophysiology: A Critical Review

“…Hence, these phenomena were reversed by lowering endogenous Ach level or by antagonizing muscarinic M1 receptors (191). On the other hand, no difference was found in electrophysiological and morphological characteristics of MSC and Ach-I between mutant and non-mutant mice (190,191). These results may provide an explanation for the efficacy of anticholinergic drugs in dystonia.…”

“…In trangenic mice expression of the mutant form of the torsinA, increased long-term potentiation (LTP) but decreased long-term depression (LTD) and depotentiation (SD). Hence, these phenomena were reversed by lowering endogenous Ach level or by antagonizing muscarinic M1 receptors (191). On the other hand, no difference was found in electrophysiological and morphological characteristics of MSC and Ach-I between mutant and non-mutant mice (190,191).…”

“…These phenomena are modulated by striatal interneurons. A series of elegant experiments performed in a rodent genetic model of DYT1 dystonia recently revealed the close interaction between cholinergic and dopaminergic transmission (68,190,191). In trangenic mice expression of the mutant form of the torsinA, increased long-term potentiation (LTP) but decreased long-term depression (LTD) and depotentiation (SD).…”

Alternative Approaches to Modeling Hereditary Dystonias

“…Despite the shortcomings of the current genetic models of dystonia, they have in some cases demonstrated that loss or mutation of a particular dystonia gene can alter the function of neurons and connectivity of brain regions [29,44,50,[60][61][62][63]. Whether or not these dysfunctions are compensatory or causal in nature remains to be established.…”