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Inhibition of endoplasmic reticulum stress reverses synaptic plasticity deficits in striatum of DYT1 dystonia mice.

ABSTRACT:

Background and objective

Striatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a^+/- in a DYT1 dystonia mouse model.

Methods

Heterozygous Tor1a^+/- mouse model for DYT1 dystonia was established. Wild-type (Tor1a^+/+, N=10) and mutant (Tor1a^+/-, N=10) mice from post-natal day P25 to P35 were randomly distributed to experimental and control groups. Patch-clamp and current-clamp recordings of SPNs were conducted with intracellular electrodes for electrophysiological analyses. Striatal changes of the direct and indirect pathways were investigated via immunofluorescence. Golgi-Cox staining was conducted to observe spine morphology of SPNs. To quantify postsynaptic signaling proteins in striatum, RNA-Seq, qRT-PCR and WB were performed in striatal tissues.

Results

Long-term depression (LTD) was failed to be induced, while long-term potentiation (LTP) was further strengthened in striatal spiny projection neurons (SPNs) from the Tor1a^+/- DYT1 dystonia mice. Spine morphology analyses revealed a significant increase of both number of mushroom type spines and spine width in Tor1a^+/- SPNs. In addition, increased AMPA receptor function and the reduction of NMDA/AMPA ratio in the postsynaptic of Tor1a^+/- SPNs was observed, along with increased ER stress protein levels in striatum of Tor1a^+/- DYT1 dystonia mice. Notably, ER stress inhibitors, tauroursodeoxycholic acid (TUDCA), could rescue LTD as well as AMPA currents.

Conclusion

The current study illustrated the role of ER stress in mediating structural and functional plasticity alterations in Tor1a^+/- SPNs. Inhibition of the ER stress by TUDCA is beneficial in reversing the deficits at the cellular and molecular levels. Remedy of dystonia associated neurological and motor functional impairment by ER stress inhibitors could be a recommendable therapeutic agent in clinical practice.

SUBMITTER: Cai H

PROVIDER: S-EPMC8436893 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.