Deciphering neural circuit dysfunction in Restless Legs Syndrome (RLS)

RLS is a neural disorder involving abnormal sensations that are reduced during motor activity, worsen at rest, and with a diurnal nighttime prevalence. Primary treatment is directed at increasing CNS dopaminergic D2-like [= D2D3D4] receptor activity. We studied the actions of dopamine and D2-like receptors on reflex function. We demonstrated that dopamine and D2-like agonists depress the monosynaptic reflex, and that at low but physiologic levels of dopamine, this modulation is mediated by D3 receptors (Clemens and Hochman 2004, attached). This dopamine-induced depression was absent in mice lacking the functional D3 receptor (D3KO) suggesting that impairments in dopamine signaling via spinal D3 receptors may account for the heightened spinal reflex amplitudes found in RLS patients. A subsequent “Medical Hypothesis” article (Clemens et al. Neurology, 67:125-130, 2006) forwarded the hypothesis that RLS reflects dysfunction in spinal dopaminergic signaling. Predicted changes in peripheral-spinal loop circuits would account for the RLS phenotype and sites of therapeutic action. Our additional electrophysiological, pharmacological, anatomical and molecular studies support this increasingly accepted model of RLS that still remains the only neural circuit model proposed (Clemens et al 2005; Zhu et al 2007, 2008). RLS as a peripheral chronic pain syndrome. We now hypothesize that RLS is a chronic muscle pain syndrome associated with vascular dysfunction caused by impaired circulation, and perhaps associated with venous insufficiency. To examine peripheral neural signaling changes, we developed an adult mouse in vitro skeletal muscle/nerve-attached preparation and are studying muscle afferent signaling changes following induced states of muscle dysfunction (intermittent hypoxia, inflammation, and venous return reductions).

CLEMENS, S., SAWCHUK, M.A., & HOCHMAN, S. Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of D3 receptor knockout mice. Neuroscience, 133(2):353-7 (2005).

CLEMENS, S. AND HOCHMAN, S. Conversion of dopamine’s modulatory actions on spinal reflexes from depression to facilitation in D3 receptor knockout mice. J Neurosci. 24:11337-45 (2004).

CLEMENS, S., RYE, D., & HOCHMAN, S. Restless Legs Syndrome: Revisiting the dopamine hypothesis from the spinal cord perspective. Neurology, 67:125-130 (2006).

ZHU,H., CLEMENS, S., SAWCHUK, M.A., & HOCHMAN, S. Expression and distribution of all dopamine receptor subtypes (D1-D5) in the mouse lumbar spinal cord: A real-time PCR and non-autoradiographic in situ hybridization study. Neuroscience, 149(4): 885-897 (2007).