The Journal of Neuroscience, September 15, 2000, 20(18):7052-7058
Deficit of Striatal Parvalbumin-Reactive GABAergic Interneurons
and Decreased Basal Ganglia Output in a Genetic Rodent Model of
Idiopathic Paroxysmal Dystonia
Manuela
Gernert,
Melanie
Hamann,
Mustapha
Bennay,
Wolfgang
Löscher, and
Angelika
Richter
Department of Pharmacology, Toxicology, and Pharmacy, School of
Veterinary Medicine, Hannover, 30559 Hannover, Germany
The underlying mechanisms of various types of hereditary dystonia,
a common movement disorder, are still unknown. Recent findings in a
genetic model of a type of paroxysmal dystonia, the
dtsz mutant hamster, pointed to striatal
dysfunctions. In the present study, immunhistochemical experiments
demonstrated a marked decrease in the number and density of
parvalbumin-immunoreactive GABAergic interneurons in all striatal
subregions of mutant hamsters. To examine the functional relevance of
the reduction of these inhibitory interneurons, the effects of the
GABAA receptor agonist muscimol on severity of
dystonia were examined after microinjections into the striatum and
after systemic administrations. Muscimol improved the dystonic syndrome
after striatal injections to a similar extent as after systemic
treatment, supporting the importance of the deficiency of striatal
GABAergic interneurons for the occurrence of the motor disturbances.
The disinhibition of striatal GABAergic projection neurons, as
suggested by recent extracellular single-unit recordings in
dtsz hamsters, should lead to an abnormal
neuronal activity in the basal ganglia output nuclei. Indeed, a
significantly decreased basal discharge rate of entopeduncular neurons
was found in dtsz hamsters. We conclude that a
deficit of striatal GABAergic interneurons leads by disinhibition of
striatal GABAergic projection neurons to a reduced activity in the
entopeduncular nucleus, i.e., to a decreased basal ganglia output. This
finding is in line with the current hypothesis about the
pathophysiology of hyperkinesias. The results indicate that striatal
interneurons deserve attention in basic and clinical research of those
movement disorders.
Key words:
animal models; basal ganglia; GABA; dyskinesia; dystonia; electrophysiology; entopeduncular nucleus; immunohistochemistry; interneurons; movement disorders; muscimol; parvalbumin; striatum
Copyright © 2000 Society for Neuroscience 0270-6474/00/20187052-07$05.00/0
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