Putative Animal Models of Restless Legs Syndrome: A Systematic Review and Evaluation of Their Face and Construct Validity

Abstract

Restless legs syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It is characterized by an urge to move the legs, which is often accompanied by periodic limb movements during sleep. RLS has a high prevalence in the population and is usually a life-long condition. While its origins remain unclear, RLS is initially highly responsive to treatment with dopaminergic agonists that target D2-like receptors, in particular D2 and D3, but the long-term response is often unsatisfactory. Over the years, several putative animal models for RLS have been developed, mainly based on the epidemiological and neurochemical link with iron deficiency, treatment efficacy of D2-like dopaminergic agonists, or genome-wide association studies that identified risk factors in the patient population. Here, we present the first systematic review of putative animal models of RLS, provide information about their face and construct validity, and report their role in deciphering the underlying pathophysiological mechanisms that may cause or contribute to RLS. We propose that identifying the causal links between genetic risk factors, altered organ functions, and changes to molecular pathways in neural circuitry will eventually lead to more effective new treatment options that bypass the side effects of the currently used therapeutics in RLS, especially for long-term therapy.

Keywords: Dopamine; Genetics; Iron; Spinal cord; Striatum.

Fig. 1

Summary of workflow to retrieve and select the existing literature on RLS animal models

Fig. 2

Repartition of selected manuscripts and their reported focus on iron deficiency, striatal circuits, and dopamine-related signaling in the RLS animal models

Fig. 3

Overview of the impact of the brain iron deficiency models on behavior and physiological functions. Blue arrows indicate an upregulation of the phenotype; red arrows indicate a downregulation

Fig. 4

Overview of the impact of the different transgenic RLS models on behavior and physiological functions. Blue arrows indicate an upregulation of the phenotype; red arrows indicate a downregulation

Fig. 5

Model of key CNS circuits involved in RLS. A Supraspinal components. Ascending fibers project to the thalamus and cortex, where the sensation of the “urge to move” the limbs is established. Descending motor pathways from the basal nuclei initiate the motor commands that underlie the leg movements and PLMS and are under modulatory control from the substantia nigra but not the dopaminergic A11 cluster. This model does not predict the origin of RLS; rather, it models how an increase in sensory or motor drive might explain the increased excitability of the neural circuitry in the brain. B Spinal cord components. Sensory afferents, with their cell bodies located in the dorsal root ganglia (DRG), project to sensory neurons (SNs) in the dorsal horn, where the incoming signals are integrated and forwarded to the brain. In parallel, the sensory signals can either directly activate spinal motoneurons (MNs) in the ventral horn or activate the spinal central pattern generators (CPGs) in the ventral intermedial areas of the spinal cord. The CPGs on both sides of the spinal cord mutually inhibit each other, thus coordinating left–right leg movements. Descending pathways from the brain, including from the dopaminergic A11 cluster, have access to and can modulate each of the spinal cord circuits independently to adjust sensory excitability, CPGs, and motor outputs