Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice

Abstract

Dystonia is common, debilitating, often medically refractory, and difficult to diagnose. The gold standard for both clinical and mouse model dystonia evaluation is subjective assessment, ideally by expert consensus. However, this subjectivity makes translational quantification of clinically-relevant dystonia metrics across species nearly impossible. Many mouse models of genetic dystonias display abnormal striatal cholinergic interneuron excitation, but few display subjectively dystonic features. Therefore, whether striatal cholinergic interneuron pathology causes dystonia remains unknown. To address these critical limitations, we first demonstrate that objectively quantifiable leg adduction variability correlates with leg dystonia severity in people. We then show that chemogenetic excitation of striatal cholinergic interneurons in mice causes comparable leg adduction variability in mice. This clinically-relevant dystonic behavior in mice does not occur with acute excitation, but rather develops after 14 days of ongoing striatal cholinergic interneuron excitation. This requirement for prolonged excitation recapitulates the clinically observed phenomena of a delay between an inciting brain injury and subsequent dystonia manifestation and demonstrates a causative link between chronic striatal cholinergic interneuron excitation and clinically-relevant dystonic behavior in mice. Therefore, these results support targeting striatal ChIs for dystonia drug development and suggests early treatment in the window following injury but prior to dystonia onset.

Mice born preterm develop gait dystonia and reduced cortical parvalbumin immunoreactivity

“…(Bonsi et al, 2011; Chintalapati et al, 2020; Eskow Jaunarajs et al, 2019, 2015; Gemperli et al, 2023; Pappas et al, 2015) By measuring leg adduction variability and amplitude, we have also shown that chronic striatal ChIN excitation can cause dystonia. (Gemperli et al, 2023) Finally, we have shown that a rat model of hypoxic-ischemic injury at human-equivalent term gestation demonstrates an increased number of striatal ChINs. (Gandham et al, 2020) However, despite this evidence implicating abnormal striatal ChIN excitation in dystonia pathogenesis, anticholinergic agents are often ineffective to treat dystonia in CP.…”

“…We propose that our highest likelihood of understanding translationally relevant dystonia pathophysiology comes by assessing clinically validated outcome measures in animal models of disease. (Gemperli et al, 2023) The role of sensorimotor parvalbumin-positive interneurons in dystonia pathogenesis after preterm birth requires further study. Though the reduced cortical parvalbumin immunoreactivity observed in this study suggests dysfunction of these interneurons, it does not necessarily suggest neuronal loss or reduced neuronal activity.…”

“…We propose that our highest likelihood of understanding translationally relevant dystonia pathophysiology comes by assessing clinically validated outcome measures in animal models of disease. (Gemperli et al, 2023)…”

“…Foot angle minimum and foot angle variance were used to measure limb adduction amplitude and variability, as we have previously demonstrated. (Bhooma R. Aravamuthan et al, 2023; Gemperli et al, 2023) All calculations were done using custom written code in MATLAB.…”

“…(Aravamuthan et al, 2021; Bhooma R. Aravamuthan et al, 2023) We have also demonstrated quantifiable metrics of leg adduction amplitude and variability track with expert assessments of dystonia severity in people with CP. (Bhooma R. Aravamuthan et al, 2023; Gemperli et al, 2023) Therefore, we propose that quantifying leg adduction amplitude and variability during gait in mice is a clinically-relevant metric of dystonia.…”