Transcript Slide 1

Session on: Animal Models of RLS
Discussion and Synopsis; Hans Hultborn
University of Copenhagen, Denmark
• My background
• What could / should be done on RLS patients
spinal /peripheral /cortical
• Animal models - problems and possibilities
Restless Legs Syndrome Foundation Scientific Meeting
Johns Hopkins Mt Washington Conf Ctr October 27-28, 2008
My own background – and interests
• Spinal cord neuronal networks – in animals and
humans
• Monoaminergic control of spinal motor programs
– locomotion
• Motoneurons – state-dependent intrinsic properties
(monoamines)
• Spinal cord injury – plasticity and recovery
RLS – a ”sensory”-driven urge to move
What does the sensitivity to DOPA tell?
That something is wrong with the dopamin system(s)? NO!
That an increased dopaminergic ”tone” can alleviate the
symptoms – by controlling other systems??
Why look for the nigro-striatal projection???
What could / should be done on RLS patients?
• Is it the A11 projection to the spinal cord that mediates the the
effect by l-DOPA?
• Give dopamin-agonists directly intratecally to the spinal cord
• Give DOPA and block dopamin receptors in the spinal cord
• (note that intrathecal pumps are ”routine” in many patients (spinal
cord lesion -- pain and spasticity)
• Is the peripheral nervous system involved? – cf Shawn Hochman
Restless legs syndrome
Revisiting the dopamine hypothesis from the spinal cord perspective
Stefan Clemens, PhD; David Rye, MD, PhD; and Shawn Hochman, PhD
Neurology. 2006; 67:125-30.
Medical Hypothesis
• This is a well formulated proposal –
ready to test – in man and animal
Record the normal activity pattern of A11 dopamin
neurons
State-dependent changes in glutamate, glycine, GABA, and
dopamine levels in cat lumbar spinal cord. Taepavarapruk N,
Taepavarapruk P, John J, Lai YY, Siegel JM, Phillips AG,
McErlane SA, Soja PJ. J Neurophysiol. 2008; 100:598-608.
Activity of medullary serotonergic neurons in freely moving
animals. Jacobs BL, Martín-Cora FJ, Fornal CA. Brain Res Res
Rev. 2002;40:45-52.
We could do with much more electrophysiological investigations on
spinal circuits – and on cortical circiuts and the cortico-spinal
projections
Karin Stiasny-Kolster and Anna Scalise - yesterday
John Rothwell at the Third International
Conference on Transcranial Magnetic and
Direct Current Stimulation in Göttingen, 2008
THE CIRCUITRY OF THE HUMAN
SPINAL CORD: ITS ROLE IN MOTOR
CONTROL AND MOVEMENT
DISORDERS By Emmanuel
Pierrot-Deseilligny and David Burke
John Rothwell is a professor of
neurophysiology at the Institute of
Neurology, Queen Square, London.
His main area of interest is transcranial
magnetic stimulation and motor
control. His group has pioneered the
use of the paired-pulse technique
(Kujirai et al 1992), interhemispheric
studies (Ferbert et al 1992).
Animal Models RLS
•
Is RLS one disease? No: idiopathic and secondary
• For me it is hard to believe that there will be a “transgenic RLS mouse” –
with the same (genetic) cause and features as for the idiopathic form of the
human disease
• More likely that we can be successful in mimicking the “secondary forms”
– and thus study the pathophysiology “downstream” to the “origin”
• RLS is primarily a condition with a “sensory-driven” urge to move – how
do we assess the “sensory” part in animal experiments? We would look
at the resulting movement!! Increased locomotor activity could be caused by
so many factors – lots of “false positives”. And there are so many rhythmic
motor activities generate even by the isolated spinal cord!!
•
Spinal ”functional units” underlying many types of
rhythmic motor activities
In decerebrate (brain-dead), spinal cats (paralyzed with
curare-like drugs) DOPA can activate the spinal locomotor
center -- the activity was monitored by recording from motor nerves
– ”fictive locomotion” Sten Grillner et al
Illustration from: Conway, B.A., Hultborn, H. and Kiehn, O. Exp Brain Res 1987; 68:643-656.
Kittens spinalized 1 week post-natal. The hind-limbs are paralyzed forelimbs under full voluntary control. Sten Grillner and coworkers
Forssberg H, Grillner S, Sjöström A. Acta Physiol Scand. 1974;92:114-20.
Forssberg H, Grillner S. Brain Res. 1973;50:184-6.
Pharmacologically evoked fictive motor patterns in the acutely
spinalized marmoset monkey (Callithrix jacchus).
Fedirchuk B, Nielsen J, Petersen N, Hultborn H. Exp Brain Res. 1998;122:351-61.
DOPA did NOT work
– but Clonidine and NMDA
Fig. 2A, B Synchronous bursts of electroneurographic
activity (shown rectified and smoothed) occurring
spontaneously after spinalization (A) and after
administration of clonidine and naloxone
(B) in the same experiment. Clonidine and naloxone
increased the amplitude (note R Per) and frequency
of these synchronous discharges
Section V. Animal Models of RLS
Chairpersons: Byron Jones and Shawn Hochman (Director involved: Dr. Earley)
• From the Bed to the Bench: what features should any model of RLS have?
(Christian Baier: 10 minutes)
• General review and critique of modeling styles: (Shawn Hochman: 5 minutes)
• RLS Models based on the dopaminergic pathway (William Ondo: 20 minutes)
• Iron insufficiency model of RLS. (John Beard: 25 minutes)
• Peripheral-spinal reflex model of RLS models. (Mauro Manconi: 15 minutes)
• Knock Outs in the iron pathway as a potential model of RLS. (Jim Connor: 15
minutes)
Open discussion by all Attendees – 10 minutes
Synopsis by Discussants: Hans Hultborn -and Marie Francoise Chesselet