ABSTRACT
GABAergic disinhibition has been suggested to play a critical role in the pathophysiology of several basal ganglia disorders, including dystonia, a common movement disorder. Previous studies have shown a deficit of striatal GABAergic interneurons (IN) in the dtsz mutant hamster, one of the few phenotypic animal models of dystonia. However, mechanisms underlying this deficit are largely unknown. In the present study, we investigated the migration and maturation of striatal IN during postnatal development (18days of age) and at age of highest severity of dystonia (33days of age) in this hamster model. In line with previous findings, the density of GAD67-positive IN and the level of parvalbumin mRNA, a marker for fast spiking GABAergic IN, were lower in the dtsz mutant than in control hamsters. However, an unaltered density of Nkx2.1 labeled cells and Nkx2.1 mRNA level suggested that the migration of GABAergic IN into the striatum was not retarded. Therefore, different factors that indicate maturation of GABAergic IN were determined. While mRNA of the KCC2 cation/chloride transporters and the cytosolic carboanhydrase VII, used as markers for the so called GABA switch, as well as BDNF were unaltered, we found a reduced number of IN expressing the alpha1 subunit of the GABAA-receptor (37.5%) in dtsz hamsters at an age of 33days, but not after spontaneous remission of dystonia at an age of 90days. Since IN shift expression from alpha2 to alpha1 subunits during postnatal maturation, this result together with a decreased parvalbumin mRNA expression suggest a delayed maturation of striatal GABAergic IN in this animal model, which might underlie abnormal neuronal activity and striatal plasticity.
Subject(s)
Corpus Striatum/growth & development , Corpus Striatum/pathology , Dystonia/pathology , GABAergic Neurons/physiology , Gene Expression Regulation, Developmental/physiology , Action Potentials/drug effects , Action Potentials/genetics , Age Factors , Animals , Animals, Newborn , Cricetinae , Disease Models, Animal , Dystonia/genetics , Female , GABAergic Neurons/enzymology , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , Gene Expression Regulation, Developmental/genetics , Glutamate Decarboxylase/metabolism , Male , Mesocricetus/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Parvalbumins/genetics , Parvalbumins/metabolism , Phenotype , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Symporters/genetics , Symporters/metabolism , Thyroid Nuclear Factor 1 , Transcription Factors/genetics , Transcription Factors/metabolism , K Cl- CotransportersABSTRACT
Dystonia is a movement disorder, characterized by involuntary muscle contractions resulting in abnormal movements and/or postures. Antidystonic effects of benzodiazepines in patients with different types of dystonia could be replicated in the dtsz mutant hamster, a phenotypic model of paroxysmal dystonia. Compounds with preferred binding at specific subunits of the gamma aminobutyric acid type A (GABAA) receptor may provide a more beneficial spectrum of effects in comparison with benzodiazepines. We therefore examined the effects of the α1ß3γ2 GABAA receptor preferring compound zolpidem (2.0-10.0mg/kg i.p.) and of the α2ß3γ2 GABAA receptor preferring compound NS11394 (3.0-30mg/kg i.p.) on the severity of dystonia in the dtsz mutant in comparison with the benzodiazepine clonazepam (0.5-1.0mg/kg i.p.). As expected, clonazepam exerted pronounced antidystonic effects. While zolpidem showed moderate beneficial effects, NS11394 significantly increased the severity of dystonia. The present results indicate for the first time that positive GABAA receptor modulators show contrary effects on dystonia dependent on their preference for alpha-subunits. The potential link between alterations in GABAA receptor subunits and GABAergic disinhibition in dystonia deserves further attention in research on the pathophysiology and therapeutic targets.
