Consensus guidelines on the construct validity of rodent models of restless legs syndrome

Salminen, Aaro V.; Clemens, Stefan; Garcı́a-Borreguero, Diego; Ghorayeb, Imad; Li, Yuqing; Manconi, Mauro; Ondo, William G.; Rye, David B.; Siegel, Jerome M.; Silvani, Alessandro; Winkelman, John W.; Allen, Richard P.; Ferré, Sergi

doi:10.1242/dmm.049615

Cited by 7 publications

(3 citation statements)

References 159 publications

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“…BID in rodents is a well-accepted animal model of RLS, which can be induced by providing a severe iron-deficient diet during the postweaning period. The model has both construct and face validity since it recapitulates several biochemical and behavioral findings of RLS ( 109 , 110 ). Using the optogenetic-microdialysis method, an increase in the sensitivity of cortico-striatal terminals to release glutamate could be demonstrated in the rat with BID, since a lower frequency of optogenetic stimulation was necessary to induce striatal glutamate release as compared to controls ( 55 ).…”

Section: D 4 R Agonists As Plausible Treatment Of ...mentioning

confidence: 86%

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants

et al. 2022

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The functional and pharmacological significance of the dopamine D4 receptor (D4R) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human DRD4 gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a D4R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D4.4R and D4.7R). DRD4 polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding D4.7R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D4R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D4R. We review the evidence conveying a significant and differential role of D4.4R and D4.7R in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic α2A receptor (α2AR)-D4R heteromers and dopamine D2 receptor (D2R)-D4R heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the D4R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.

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Section: D 4 R Agonists As Plausible Treatment Of ...mentioning

confidence: 86%

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants

et al. 2022

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“…In addition to the future directions listed throughout the review, other directions are worth exploring. For example, animal models of RLS have targeted iron deficiency, the dopaminergic system [ 111 112 113 ] as well as the endogenous opiate system [ 83 84 85 ]. Vitamin D deficiency models have been created, but to our knowledge the clinical or biochemical particularities of RLS have not been investigated in these models [ 114 115 ].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D and Restless Legs Syndrome: A Review of Current Literature

Cederberg¹,

Silvestri²,

Walters³

2023

Tremor and Other Hyperkinetic Movements

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This review presents a detailed summary of the current literature regarding RLS and vitamin D deficiency. To our knowledge it is the first review of its kind. We review the prevalence of vitamin D deficiency in RLS as well as the evidence for the use of vitamin D supplementation in RLS management. We further examine the literature for proteomic and genetic evidence of a role for vitamin D in the pathogenesis of RLS. An alteration in vitamin D binding protein in RLS is one of the most consistent findings in the proteomic studies. Furthermore, we examine the interaction of vitamin D with calcium, phosphorus, and parathyroid hormone and the possible role of these connections in RLS. We also explore the possible nexus between RLS and vitamin D in renal disease, cardiovascular and cerebrovascular disease as well as inflammation. In addition, we review the potential interaction between vitamin D and RLS with iron, dopamine and other neurotransmitter systems including the endogenous opiate, serotoninergic, glutamatergic and adenosinergic systems. We also explore the role of vitamin D in RLS Augmentation (i.e., the paradoxical worsening of RLS symptoms when dopaminergic agents are used as a therapy for RLS). Although the literature is not entirely consistent in affirming vitamin D deficiency in RLS or the amelioration of RLS symptoms with vitamin D therapy, the collective studies overall indicate that vitamin D deficiency is common enough in RLS patients to suggest that RLS patients should have their vitamin D levels checked and any deficiency corrected as a standard of care. HighlightsPatients with Restless Legs Syndrome (RLS) may be deficient in vitamin D and therapy with vitamin D may ameliorate RLS. We present the first review dedicated solely to evaluating the relationship between RLS and vitamin D and present a case for the role of vitamin D in RLS pathogenesis.

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“…RLS is a multifaceted neurological disorder with a wide range of both genetic and non-genetic components. The interplay between these different factors makes it difficult to identify a singular animal model that combines face validity with construct validity ( 52 , 53 ). Several risk genes have been identified in genome-wide association studies, and the mutation of these risk gene orthologs in mice showed phenotypes relevant to RLS, such as alterations in iron metabolism, dopamine function, sensory perception, and sleep [e.g., MEIS1: ( 33 , 54 , 55 ); BTBD9: ( 56–58 ); PTPRD: ( 18 ); D3KO: ( 30 , 33 , 59 , 60 )].…”

Section: Discussionmentioning

confidence: 99%

Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of Restless Legs Syndrome

Woods,

Basco,

Clemens

2023

Front. Neurol.

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Restless Legs Syndrome (RLS) is a common sensorimotor and a sleep disorder that affects 2.5–10% of the European and North American populations. RLS is also often associated with periodic leg movements during sleep (PLMS). Despite ample evidence of genetic contributions, the underlying mechanisms that elicit the sensory and motor symptoms remain unidentified. Clinically, RLS has been correlated with an altered central iron metabolism, particularly in the brain. While several animal models have been developed to determine the outcome of an altered iron homeostasis on brain function, the potential role of an altered iron homeostasis on sleep and sensorimotor circuits has not yet been investigated. Here, we utilize a mouse model to assess the effects of an iron-deficient (ID) but non-anemic state on sleep time and episodes, and sensorimotor reflexes in male and female mice. We found that animals on the ID diet displayed an increased expression of the transferrin receptor in the spinal cord, confirming the results of previous studies that focused only on the impact of ID in the brain. We also demonstrate that the ID diet reduced hematocrit levels compared to controls but not into the anemic range, and that animals on the ID diet exhibited RLS-like symptoms with regard to sleep onset and spinal cord reflex excitability. Interestingly, the effects on the spinal cord were stronger in females than in males, and the ID diet-induced behaviors were rescued by the return of the animals to the control diet. Taken together, these results demonstrate that diet-induced ID changes to CNS function are both inducible and reversible, and that they mimic the sleep and sensorimotor RLS symptoms experienced in the clinic. We therefore propose replacing the commonly used phrase “brain iron deficiency” (BID) hypothesis in the RLS research field with the term “iron deficiency in the central nervous system” (ID-CNS), to include possible effects of altered iron levels on spinal cord function.

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Consensus guidelines on the construct validity of rodent models of restless legs syndrome

Cited by 7 publications

References 159 publications

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants

Vitamin D and Restless Legs Syndrome: A Review of Current Literature

Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of Restless Legs Syndrome

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