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.
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.