[Abstract Title]. - Society for Neuroscience

Title: Rapid onset dystonia-parkinsonism requires interaction between dysfunctional cerebellar
and basal ganglia motor control loops
Authors: *D. P. CALDERON, K. KHODAKHAH;
Neurosci., Albert Einstein Col. Med., Bronx, NY
Abstract: Dystonia is characterized by co-contraction of opposing agonist and antagonist
muscles and can be acquired or genetic in origin. One of the most intriguing types of dystonia is
Rapid-onset Dystonia-Parkinsonism (RDP) or DYT12, which is caused by mutations in the α3
isoform of the sodium/potassium ATPase pump (sodium pump). Subjects carrying this mutated
gene show a sudden onset of symptoms often triggered by an extremely stressful
experience.These symptoms typically include dystonia, parkinsonism, dysarthria, dysphagia,
slurred speech, postural instability, and wide stance.
Even though the genetic basis of this disorder is known, it is currently unclear how dysfunction
of the sodium pump results in RDP. Furthermore, the anatomical brain structures that
malfunction in this disease have not been identified. Many of the symptoms such as dystonia and
parkinsonism suggest the involvement of the basal ganglia in this disorder. However, other
prominent symptoms such as a wide stance or slurred speech are most frequently caused by
cerebellar dysfunction. We took advantage of a potent and exquisitely selective blocker of
sodium pumps to generate a pharmacological animal model of RDP in mice. We found that
concurrent local chronic perfusion of the basal ganglia and the cerebellum with ouabain
concentrations that partially blocked sodium pumps accurately reproduced the features of RDP.
Prior to a stressful event the mice showed some reduced locomotion and mild ataxia/gait
disturbance. However, only extreme stress triggered severe dystonia, as determined by
electromyogram recordings. Dystonia persisted for days after the stressful episode. Remarkably,
we found that an interaction between dysfunctional basal ganglia and cerebellar motor loops is
essential to reproduce RDP. While perfusion of ouabain in the basal ganglia or cerebellum alone
produced clear, but distinct, motor phenotypes, stress did not worsen these phenotypes or trigger
dystonia. This animal model highlights the concomitant involvement of cerebellar and basal
ganglia motor control loops in RDP and may be valuable in understanding its etiology.
Disclosures: D.P. Calderon, None; K. Khodakhah, None.
Poster
248. Dystonia
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 248.19/U18
Topic: C.03.j. Dystonia