Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome
Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previou...
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MDPI AG
2022-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/5/1489 |
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| author | Matilde S. Rodrigues Samira G. Ferreira César Quiroz Christopher J. Earley Diego García-Borreguero Rodrigo A. Cunha Francisco Ciruela Attila Köfalvi Sergi Ferré |
| author_facet | Matilde S. Rodrigues Samira G. Ferreira César Quiroz Christopher J. Earley Diego García-Borreguero Rodrigo A. Cunha Francisco Ciruela Attila Köfalvi Sergi Ferré |
| author_sort | Matilde S. Rodrigues |
| collection | DOAJ |
| description | Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previous studies with the BID-rodent model of RLS demonstrated increased sensitivity of cortical pyramidal cells to release glutamate from their striatal nerve terminals driving striatal circuits, a correlative finding of the cortical motor hyperexcitability of RLS patients. It was also found that BID in rodents leads to changes in the adenosinergic system, a downregulation of the inhibitory adenosine A<sub>1</sub> receptors (A<sub>1</sub>Rs) and upregulation of the excitatory adenosine A<sub>2A</sub> receptors (A<sub>2A</sub>Rs). It was then hypothesized, but not proven, that the BID-induced increased sensitivity of cortico-striatal glutamatergic terminals could be induced by a change in A<sub>1</sub>R/A<sub>2A</sub>R stoichiometry in favor of A<sub>2A</sub>Rs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A<sub>1</sub>Rs and A<sub>2A</sub>Rs in cortico-striatal and thalamo-striatal glutamatergic terminals (labeled with vesicular glutamate transporters VGLUT1 and VGLUT2, respectively) of control and BID rats. It could be demonstrated that BID (determined by measuring transferrin receptor density in the brain) is associated with a selective decrease in the A<sub>1</sub>R/A<sub>2A</sub>R ratio in VGLUT1 positive-striatal terminals. |
| first_indexed | 2024-03-09T20:30:14Z |
| format | Article |
| id | doaj.art-84996bcbe2df4dbba35686e4de4c23b3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T20:30:14Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-84996bcbe2df4dbba35686e4de4c23b32023-11-23T23:25:07ZengMDPI AGMolecules1420-30492022-02-01275148910.3390/molecules27051489Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs SyndromeMatilde S. Rodrigues0Samira G. Ferreira1César Quiroz2Christopher J. Earley3Diego García-Borreguero4Rodrigo A. Cunha5Francisco Ciruela6Attila Köfalvi7Sergi Ferré8CNC-Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, PortugalCNC-Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, PortugalIntegrative Neurobiology Section, National Institute on Drug Abuse, Baltimore, MD 21224, USADepartment of Neurology, Johns Hopkins University, Baltimore, MD 21224, USASleep Research Institute, 28036 Madrid, SpainCNC-Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, PortugalPharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L’Hospitalet de Llobregat, SpainCNC-Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, PortugalIntegrative Neurobiology Section, National Institute on Drug Abuse, Baltimore, MD 21224, USABrain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previous studies with the BID-rodent model of RLS demonstrated increased sensitivity of cortical pyramidal cells to release glutamate from their striatal nerve terminals driving striatal circuits, a correlative finding of the cortical motor hyperexcitability of RLS patients. It was also found that BID in rodents leads to changes in the adenosinergic system, a downregulation of the inhibitory adenosine A<sub>1</sub> receptors (A<sub>1</sub>Rs) and upregulation of the excitatory adenosine A<sub>2A</sub> receptors (A<sub>2A</sub>Rs). It was then hypothesized, but not proven, that the BID-induced increased sensitivity of cortico-striatal glutamatergic terminals could be induced by a change in A<sub>1</sub>R/A<sub>2A</sub>R stoichiometry in favor of A<sub>2A</sub>Rs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A<sub>1</sub>Rs and A<sub>2A</sub>Rs in cortico-striatal and thalamo-striatal glutamatergic terminals (labeled with vesicular glutamate transporters VGLUT1 and VGLUT2, respectively) of control and BID rats. It could be demonstrated that BID (determined by measuring transferrin receptor density in the brain) is associated with a selective decrease in the A<sub>1</sub>R/A<sub>2A</sub>R ratio in VGLUT1 positive-striatal terminals.https://www.mdpi.com/1420-3049/27/5/1489adenosine A<sub>1</sub> receptoradenosine A<sub>2A</sub> receptorrestless legs syndromebrain iron deficiencystriatumcortico-striatal terminals |
| spellingShingle | Matilde S. Rodrigues Samira G. Ferreira César Quiroz Christopher J. Earley Diego García-Borreguero Rodrigo A. Cunha Francisco Ciruela Attila Köfalvi Sergi Ferré Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome Molecules adenosine A<sub>1</sub> receptor adenosine A<sub>2A</sub> receptor restless legs syndrome brain iron deficiency striatum cortico-striatal terminals |
| title | Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome |
| title_full | Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome |
| title_fullStr | Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome |
| title_full_unstemmed | Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome |
| title_short | Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome |
| title_sort | brain iron deficiency changes the stoichiometry of adenosine receptor subtypes in cortico striatal terminals implications for restless legs syndrome |
| topic | adenosine A<sub>1</sub> receptor adenosine A<sub>2A</sub> receptor restless legs syndrome brain iron deficiency striatum cortico-striatal terminals |
| url | https://www.mdpi.com/1420-3049/27/5/1489 |
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