Lüttig Anika, Perl Stefanie, Franz Denise, Kotyra Malin, Morawski Markus, Köhling Rüdiger, Richter Angelika
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 15, Leipzig 04103, Germany.
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 15, Leipzig 04103, Germany.
Brain Res Bull. 2025 Oct 1;230:111486. doi: 10.1016/j.brainresbull.2025.111486. Epub 2025 Jul 28.
Maladaptive plasticity is thought to be involved in dystonia and paroxysmal dyskinesia, which often occur in early life in children and in animals. While the pathophysiology of these disorders is poorly understood, canine paroxysmal dyskinesia can be caused by a deletion in the gene, encoding the brain-specific component of the extracellular matrix (ECM) brevican (Brev). Brev plays a crucial role in the maturation of parvalbumin-reactive GABAergic interneurons (PV). Therefore, in the present study we investigated whether abnormal expression of Brev coincides with age-dependent dystonia in the dt hamster, a model of paroxysmal dystonia in which previous studies indicated altered maturation of striatal PV. In addition, we examined if changes in Brev expression might be involved in antidystonic effects of deep brain stimulations (DBS) of the entopeduncular nucleus (EPN; analogue of the globus pallidus internus in primates). In comparison to age-matched non-dystonic control hamsters, dt mutant hamsters showed a higher Brev expression in the ventral thalamic nucleus (21 and 35 days) and a lower number of Brev cells in the motor cortex (35 days). Furthermore, there were age-dependent differences especially a lower number of Brev cells in the motor cortex and a higher single cell intensity in the EPN (each in comparison to 21 and 90 days) at the age of 35 days (the age of maximum severity of dystonia). Brevican intensity seems to decrease at the age of 90 days (the age of spontaneous remission of dystonia) in some brain regions. EPN-DBS for 3 h was probably too short to induce significant changes as an explanation for recent electrophysiological data on cortico-striatal responses after DBS, but in sham-stimulated animal groups, the genotype-differences in motor cortex and thalamus could be confirmed. The present findings suggest that ECM warrant consideration in dystonia research.
适应性不良的可塑性被认为与肌张力障碍和阵发性运动障碍有关，这些疾病常在儿童和动物的早期生活中出现。虽然这些疾病的病理生理学仍知之甚少，但犬类阵发性运动障碍可能由编码细胞外基质（ECM）短蛋白聚糖（Brev）脑特异性成分的基因缺失引起。Brev在小白蛋白反应性γ-氨基丁酸能中间神经元（PV）的成熟过程中起关键作用。因此，在本研究中，我们调查了Brev的异常表达是否与dt仓鼠（一种阵发性肌张力障碍模型，先前的研究表明其纹状体PV成熟改变）中年龄依赖性肌张力障碍一致。此外，我们研究了Brev表达的变化是否可能参与了内豆状核（EPN；灵长类动物苍白球内侧部的类似物）深部脑刺激（DBS）的抗肌张力障碍作用。与年龄匹配的非肌张力障碍对照仓鼠相比，dt突变仓鼠在腹侧丘脑核（21天和35天）中Brev表达较高，而在运动皮层中Brev细胞数量较少（35天）。此外，在35天（肌张力障碍最严重的年龄）存在年龄依赖性差异，尤其是运动皮层中Brev细胞数量较少，而EPN中单个细胞强度较高（均与21天和90天相比）。在90天（肌张力障碍自发缓解的年龄）时，一些脑区的短蛋白聚糖强度似乎降低。EPN-DBS持续3小时可能太短，无法诱导显著变化以解释近期关于DBS后皮质-纹状体反应的电生理数据，但在假刺激动物组中，可以证实运动皮层和丘脑中的基因型差异。目前的研究结果表明，细胞外基质在肌张力障碍研究中值得考虑。
