TY - JOUR
T1 - Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals
T2 - Implications for Restless Legs Syndrome
AU - Rodrigues, Matilde S.
AU - Ferreira, Samira G.
AU - Quiroz, César
AU - Earley, Christopher J.
AU - García-Borreguero, Diego
AU - Cunha, Rodrigo A.
AU - Ciruela, Francisco
AU - Köfalvi, Attila
AU - Ferré, Sergi
N1 - Funding Information:
Funding: This work was financed by La Caixa Foundation (LCF/PR/HP17/52190001) and the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Program, and through the COMPETE 2020—Operational Program for Competitiveness and Internationalization and Portuguese national funds UIDB/04539/2020 and UIDP/04539/2020 of FCT—Fundação para a Ciência e a Tecnologia. C.Q. and S.F. were supported by the intramural funds of the National Institute on Drug Abuse.
Funding Information:
This work was financed by La Caixa Foundation (LCF/PR/HP17/52190001) and the Euro-pean Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Program, and through the COMPETE 2020?Operational Program for Competitiveness and Internationalization and Portuguese national funds UIDB/04539/2020 and UIDP/04539/2020 of FCT?Funda??o para a Ci?ncia e a Tecnologia. C.Q. and S.F. were supported by the intramural funds of the National Institute on Drug Abuse.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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 A1 receptors (A1 Rs) and upregulation of the excitatory adenosine A2A receptors (A2A 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 A1 R/A2A R stoichiometry in favor of A2A Rs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A1 Rs and A2A 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 A1 R/A2A R ratio in VGLUT1 positive-striatal terminals.
AB - 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 A1 receptors (A1 Rs) and upregulation of the excitatory adenosine A2A receptors (A2A 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 A1 R/A2A R stoichiometry in favor of A2A Rs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A1 Rs and A2A 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 A1 R/A2A R ratio in VGLUT1 positive-striatal terminals.
KW - Adenosine A receptor
KW - Brain iron deficiency
KW - Cortico-striatal terminals
KW - Restless legs syndrome
KW - Striatum
KW - Thalamo-striatal terminals
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U2 - 10.3390/molecules27051489
DO - 10.3390/molecules27051489
M3 - Article
C2 - 35268590
AN - SCOPUS:85125172886
SN - 1420-3049
VL - 27
JO - Molecules
JF - Molecules
IS - 5
M1 - 1489
ER -