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.
Highlights
DYT1 dystonia, which is a complex neurological condition characterized by abnormal involuntary motors or postures [1], is usually attributed to a GAG base-pair deletion of DYT1 (Tor1a) gene encoding Tor1a protein [2]
The current study illustrated the role of endoplasmic reticulum (ER) stress in mediating structural and functional plasticity alterations in Tor1a+/- spiny projection neurons (SPNs)
Inhibition of the ER stress by tauroursodeoxycholic acid (TUDCA) is beneficial in reversing the deficits at the cellular and molecular levels
Summary
DYT1 dystonia, which is a complex neurological condition characterized by abnormal involuntary motors or postures [1], is usually attributed to a GAG base-pair deletion of DYT1 (Tor1a) gene encoding Tor1a protein [2]. Symptoms of abnormal motor learning have been observed in Tor1a mutation (Tor1a+/-) carriers without evident clinical manifestation, which further supports the opinion that impaired synaptic plasticity might be an inherent feature of dystonia [6]. Impaired striatal synaptic plasticity has been explored in dystonia rodent models, including heterozygous DYT1 knock-in mice [7, 8], which presented a remarkable similarity to the studies in dystonia patients [9]. The current evidence supports the judgement that DYT1 dystonia could be regarded as a neurodevelopmental disease with impaired striatal plasticity and motor dysfunction. 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. Golgi-Cox staining was conducted to observe spine morphology of SPNs
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