Objective: To determine whether the ablation of Nkx2.1 derived striatal interneurons (SI) in mice produces Tourette-like phenotypes including abnormal movements and perseverative behaviors.

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, often accompanied by comorbid conditions such as obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). While symptoms typically attenuate during adolescence, some patients experience persistent, treatment-resistant tics [1]. The pathophysiology of TS remains poorly understood, but studies show a reduced number of PV+, nNOS+ and ChAT+ SI in TS patients [2-4]. Attempts to model TS in mice by ablating specific subtypes of SI failed to induce tic-like movements [5-9]. Notably, all the SI subtypes affected in TS derive from cell precursors expressing the transcription factor Nkx2.1 [10].

Method: In order to reproduce more closely the striatal changes reported in patients, we performed a combined ablation of multiple SI subtypes using a Cre/loxP transgenic system to express human diphtheria toxin receptor (hDTR) in the Nkx2.1+ cell lineage. Intrastriatal diphtheria toxin (DT) administration produced a specific ablation of Nkx2.1+ SI in mice expressing hDTR but not in control Cre- mice. We developed a Mouse Tic Severity Scale (MTSS) based on the Yale Tics Severity Scale used in clinical settings to measure motor tics [11].

Results: Lesioned mice developed abnormal involuntary movements resembling motor tics and had a higher MTSS score than controls as determined by blind observers (Median [IQR]: 8.5 [3-14.6], n=46; 4 [2-6.5], n=43, respectively; Mann-Whitney; p<0.0001). Additionally, lesioned mice displayed behaviors consistent with TS comorbidities including repetitive behaviors and hyperactivity, with a 60% increase of head pokes (t-test; p=0.020), increased distance traveled in an open field test (t-test; p=0.013) and more time doing vertical exploration (rearing) in a small chamber (Mann-Whitney; p=0.006) compared to controls.

Conclusion: Ablation of Nkx2.1+ striatal interneurons leads to spontaneous tic-like movements, hyperlocomotion and perseverative behaviors resembling TS symptoms. These findings suggest that Nkx2.1-derived SI play a critical role in motor control and TS pathophysiology.

Graphical abstract

References: 1. Hirschtritt et al, JAMA Psychiatry 72, 325 (2015); 2. Kalanithi et al, PNAS 102, 13307–12 (2005); 3. Kataoka et al, J. Comp. Neurol. 518, 277–91 (2010); 4. Lennington et al, Biol. Psychiatry 79, 372–82 (2016); 5. Xu et al, PNAS 112, 893–8 (2015); 6. Martos et al, J. Neurosci. 37, 2849–58 (2017); 7. Xu et al, Neuroscience 324, 321–9 (2016); 8. Kaneko et al, Science 289, 633–7 (2000); 9. Owen et al, Cell 172, 683–95 (2018); 10. Marin et al, J. Neurosci. 20, 6063–76 (2000); 11. Leckman et al, J. Am. Acad. Child Adolesc. Psychiatry 28, 566-73 (1989).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tourette-like-phenotypes-following-combined-striatal-interneuron-loss/