P 76 Maturation deficits in striatal interneurons in a phenotypic model of dystonia

GABAergic disinhibition has been suggested to play a critical role in the pathophysiology of several basal ganglia disorders, including dystonia, a common incurable movement disorder characterized by involuntary muscle contractions resulting in abnormal movements and/or postures. 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. The resulting lack of inhibition of striatal projection neurons is likely involved in development of dystonic episodes which is corroborated by antidystonic effects of GABA potentiating drugs in the animal model and in dystonia patients. However, mechanisms underlying this deficit in striatal IN are largely unknown. In the present study, we investigated the migration and maturation of striatal IN during postnatal development (18 days of age) and at age of highest severity of dystonia (33 days of age) in the dtsz hamster by immunohistochemistry and real time PCR. 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 mutant hamsters than in controls. However, an unaltered density of Nkx2.1 labeled cells and Nkx2.1 mRNA level indicated that the migration of GABAergic IN into the striatum was not retarded. KCC2 cation/chloride transporter and cytosolic carboanhydrase VII mRNA expression, used as markers for maturation of striatal GABAergic signaling, as well as expression of BDNF were unaltered. However, we found a reduced number of IN expressing the alpha1 subunit of the GABAA-receptor (37.5%) in dtsz hamsters at an age of 33 days, but not after spontaneous remission of dystonia at an age of 90 days. 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. 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.