[Abstract Title]. - Society for Neuroscience

Topic: C.03.j. Dystonia
Support: Grant from the Forschungskommission of the Freie Universität Berlin
Title: Pharmacological manipulations of the dopaminergic system in a transgenic mouse model
of early-onset dystonia
Authors: N. LANGE 1 , M. HAMANN 1 , P. SHASHIDHARAN 2 , *A. RICHTER 1 ;
1 Dept Pharmacol& Toxicol, Depart. Vet. Med. Fu Berlin, Berlin, Germany; 2 Dept. of Neurol.,
Mount Sinai Sch. of Med., New York, NY
Abstract: A trinucleotide deletion (ΓGAG) in the DYT1 gene is implicated in early-onset
torsion dystonia. This movement disorder is characterized by involuntary, sustained muscle
contractions and has an autosomal dominant inheritance pattern with ~30-40% penetrance. The
mutation leads to the loss of a glutamic acid residue in the carboxy region of torsinA. The
pathophysiological role of the mutation in causing dystonia is poorly understood. Well
characterized animal models can help to understand the underlying mechanisms and thereby to
develop new therapeutic strategies. Shashidharan et al. described a transgenic mouse model
(DYT1 mice) with the human gene defect and overexpression of mutant torsinA, leading to
hyperactivity, dystonic-like movements, abnormal shaking of the head and circling behavior. In
the present study, different behavioral investigations combined with the administration of 100
mg/kg L-DOPA + 10 mg/kg carbidopa (CD) in DYT1 and control mice should clarify the
pathophysiological role of the dopaminergic system. It was described that the severity of
symptoms increased with age in the DYT1 mice (Shashidharan et al., 2005). Thus, all
experiments were done in 3 and 6 month old DYT1 and age-matched control mice. DYT1 mice
in both age periods showed hyperactivity in comparison to controls. The administration of L-
DOPA/CD reduced the locomotor activity in both, DYT1 and age-matched control mice in
comparison to vehicle treatment. Naïve and vehicle treated transgenic mice at the age of 3 month
expressed higher neuromuscular strength in the grip strength test. The application of L-
DOPA/CD reduced the neuromuscular strength in 3 month old DYT1 mice, while no effect
could be observed in controls. In 6 month old mice, no significant differences between the
different animal or treatment groups could be observed. In comparison to vehicle control, the
administration of L-DOPA/CD reduced the latency to fall from the rotarod in both, transgenic
and control mice without age-dependency. The severity of dystonic-like movements, which was
rated by a score-system, increased after the administration of L-DOPA/CD in DYT1 mice in
both tested age periods. However, the present data revealed that also wild-type mice exhibit
similar movements. The present results may indicate that the dopaminergic system is affected in
DYT1 mice, although the observed differences to control animals were only moderate. Ongoing
pharmacological studies with dopamine receptor agonists and antagonists as well as a dopamine
reuptake inhibitor have to further clarify the relevance of distinct parts of the dopaminergic
system.
Supported by a grant from the FK of the Freie Universität Berlin.
Disclosures: N. Lange, None; M. Hamann, None; A. Richter , None; P. Shashidharan, None.