Chronic Striatal Cholinergic Interneuron Excitation Causes Cerebral Palsy-Related Dystonic Behavior in Mice.

IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY
Kat Gemperli, Xinguo Lu, Keerthana Chintalapati, Alyssa Rust, Rishabh Bajpai, Nathan Suh, Joanna Blackburn, Rose Gelineau-Morel, Michael C Kruer, Dararat Mingbunjerdsuk, Jennifer O'Malley, Laura Tochen, Jeff L Waugh, Steve Wu, Timothy Feyma, Joel Perlmutter, Steven Mennerick, Jordan G McCall, Bhooma R Aravamuthan
{"title":"Chronic Striatal Cholinergic Interneuron Excitation Causes Cerebral Palsy-Related Dystonic Behavior in Mice.","authors":"Kat Gemperli, Xinguo Lu, Keerthana Chintalapati, Alyssa Rust, Rishabh Bajpai, Nathan Suh, Joanna Blackburn, Rose Gelineau-Morel, Michael C Kruer, Dararat Mingbunjerdsuk, Jennifer O'Malley, Laura Tochen, Jeff L Waugh, Steve Wu, Timothy Feyma, Joel Perlmutter, Steven Mennerick, Jordan G McCall, Bhooma R Aravamuthan","doi":"10.1002/ana.27299","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Mouse models of genetic dystonias have demonstrated abnormal striatal cholinergic interneuron excitability, but do not consistently demonstrate subjective dystonic features. To determine whether striatal cholinergic interneuron excitation can cause potentially dystonic motor behaviors, we first determined features correlated specifically with dystonia severity in people and then determined whether these features emerged in mice following striatal cholinergic interneuron excitation.</p><p><strong>Methods: </strong>Eight movement disorders experts rated dystonia severity in 193 videos of people with cerebral palsy doing a seated task. Leg adduction variability metrics, which are known to correlate with leg dystonia severity during gait, were quantified in these videos of seated tasks. Metrics significantly associated with leg dystonia severity during seated tasks in people were then quantified in mice and compared between mice who underwent chemogenetic striatal cholinergic interneuron excitation (n = 17) and mice who did not (n = 17).</p><p><strong>Results: </strong>Leg adduction variability correlated well with experts' leg dystonia severity scores in people. Leg adduction variability was also significantly increased in mice that underwent striatal cholinergic interneuron excitation compared to mice that did not (p < 0.05). This difference was not present with acute excitation and emerged only after 14 days of ongoing excitation.</p><p><strong>Interpretation: </strong>We demonstrate that leg adduction variability correlates with leg dystonia severity in people with cerebral palsy and that chronic, but not acute, striatal cholinergic interneuron excitation can cause leg adduction variability in mice. These results support targeting striatal cholinergic interneurons for dystonia drug development and demonstrate the potential value of using quantifiable leg adduction metrics to study dystonia pathophysiology. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1000,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ana.27299","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Objective: Mouse models of genetic dystonias have demonstrated abnormal striatal cholinergic interneuron excitability, but do not consistently demonstrate subjective dystonic features. To determine whether striatal cholinergic interneuron excitation can cause potentially dystonic motor behaviors, we first determined features correlated specifically with dystonia severity in people and then determined whether these features emerged in mice following striatal cholinergic interneuron excitation.

Methods: Eight movement disorders experts rated dystonia severity in 193 videos of people with cerebral palsy doing a seated task. Leg adduction variability metrics, which are known to correlate with leg dystonia severity during gait, were quantified in these videos of seated tasks. Metrics significantly associated with leg dystonia severity during seated tasks in people were then quantified in mice and compared between mice who underwent chemogenetic striatal cholinergic interneuron excitation (n = 17) and mice who did not (n = 17).

Results: Leg adduction variability correlated well with experts' leg dystonia severity scores in people. Leg adduction variability was also significantly increased in mice that underwent striatal cholinergic interneuron excitation compared to mice that did not (p < 0.05). This difference was not present with acute excitation and emerged only after 14 days of ongoing excitation.

Interpretation: We demonstrate that leg adduction variability correlates with leg dystonia severity in people with cerebral palsy and that chronic, but not acute, striatal cholinergic interneuron excitation can cause leg adduction variability in mice. These results support targeting striatal cholinergic interneurons for dystonia drug development and demonstrate the potential value of using quantifiable leg adduction metrics to study dystonia pathophysiology. ANN NEUROL 2025.

慢性纹状体胆碱能神经元间兴奋引起小鼠脑瘫相关张力障碍行为。
目的:遗传性肌张力障碍小鼠模型显示纹状体胆碱能神经元间兴奋性异常,但不一致地显示主观肌张力障碍特征。为了确定纹状体胆碱能中间神经元兴奋是否会导致潜在的肌张力障碍运动行为,我们首先确定了与人肌张力障碍严重程度相关的特征,然后确定纹状体胆碱能中间神经元兴奋后这些特征是否出现在小鼠身上。方法:8位运动障碍专家对193个脑瘫患者坐着的视频进行了张力障碍严重程度评分。腿内收变异性指标,已知与步态中腿部肌张力障碍的严重程度相关,在这些坐着任务的视频中被量化。然后在小鼠中量化了与人坐着时腿部肌张力障碍严重程度显著相关的指标,并比较了接受化学发生纹状体胆碱能中间神经元兴奋的小鼠(n = 17)和未接受化学发生纹状体胆碱能中间神经元兴奋的小鼠(n = 17)。结果:腿内收变异性与专家评定的人腿肌张力障碍严重程度评分有良好的相关性。与未接受纹状体胆碱能中间神经元兴奋的小鼠相比,接受纹状体胆碱能中间神经元兴奋的小鼠腿部内收变异性也显著增加(p)解释:我们证明,在脑瘫患者中,腿部内收变异性与腿部肌张力障碍的严重程度相关,并且慢性(而非急性)纹状体胆碱能中间神经元兴奋可导致小鼠腿部内收变异性。这些结果支持针对纹状体胆碱能中间神经元开发肌张力障碍药物,并证明了使用可量化的腿内收指标研究肌张力障碍病理生理的潜在价值。Ann neurol 2025。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Annals of Neurology
Annals of Neurology 医学-临床神经学
CiteScore
18.00
自引率
1.80%
发文量
270
审稿时长
3-8 weeks
期刊介绍: Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信