Session Time: 12:00pm-1:30pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To further define the pathophysiology of the reduction of striatal interneurons in an animal model of dystonia and to develop novel therapeutic strategies targeting specific subunits of the GABAA receptor (GABAAR).
Background: Dystonia is characterized by intermittent and prolonged muscle contractions resulting in involuntary movements and/or abnormal postures. Although benzodiazepines can improve the symptoms, tolerance and side effects limit their use. Therefore there is need for novel therapeutics based on pathophysiological mechanisms. There is evidence for dysregulation of striatal signaling in dystonia, which could be due to reduction of GABAergic striatal interneurons (IN). In the dtsz mutant hamster, a model of paroxysmal dystonia, immunolabeled IN were reduced at the age of maximum severity of dystonia, but not after spontaneous remission. Using the IN specific marker homeoboxprotein nkx 2.1 we showed that the neurons were present in the striatum but did not express their specific proteins (i.e. parvalbumine), a sign for delayed maturation.
Methods: Here we determined the maturation of striatal GABAergic neurons in the dtsz hamster compared to controls with immunohistochemistry and quantitative PCR. We further tested specific GABAAR agonists for therapeutic potential.
Results: KCC2 and CAVII mRNA, markers for the GABA-switch, were unchanged in 18 and 33 day old mutant hamsters, indicating that there is no general delay in GABAergic maturation. We found a 46% decrease in neurons expressing the specific GABAAR subunit alpha1. A lower immunoreactive intensity was restricted to the somata of dorsomedial striatal IN (32%) of dtsz hamsters, indicating both a reduced density as well as a delayed maturation. The alpha1 GABAAR preferring compound zolpidem (2.0 and 10.0 mg/kg i.p.) exerted moderate antidystonic effects compared to the benzodiazepine clonazepam (0.5 and 1.0 mg/kg i.p.) in the dtsz hamster. Examinations of alpha2 GABAAR preferring compounds are ongoing.
Conclusions: Our studies indicate that there is a delayed maturation of striatal GABAergic interneurons which express alpha1 GABAAR subunits in the dystonic hamster. Changes in alpha1 GABAAR subunit expression and differences in the antidystonic efficacy of zolpidem and clonazepam indicate that further investigations on the role of GABAAR subunits could lead to new therapeutic approaches for the treatment of dystonia.
To cite this abstract in AMA style:F. Richter, C. Bode, C. Spröte, A. Bauer, A. Richter. Therapeutic potential of compounds preferring specific GABAA receptor subunits for the treatment of dystonia? [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/therapeutic-potential-of-compounds-preferring-specific-gabaa-receptor-subunits-for-the-treatment-of-dystonia/. Accessed March 2, 2024.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/therapeutic-potential-of-compounds-preferring-specific-gabaa-receptor-subunits-for-the-treatment-of-dystonia/