Abstract
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 (A1Rs) and upregulation of the excitatory adenosine A2A receptors (A2ARs). 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 A1R/A2AR stoichiometry in favor of A2ARs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A1Rs and A2ARs 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 A1R/A2AR ratio in VGLUT1 positive-striatal terminals.
Highlights
Restless legs syndrome (RLS) is a common sensorimotor disorder, whose basic components include a primary sensory experience, akathisia, and in about 80% of patients a secondary motor component, periodic leg movements during sleep (PLMS), can be found [1,2]
We evaluated the frequency of striatal terminals that were positive for vesicular transporter VGLUT1 (VGLUT1+), VGLUT2 (VGLUT2+), A1 receptors (A1Rs) (A1R+) or A2A receptors (A2ARs) (A2AR+) and the total A1R+/A2AR+ ratio
Taking into account the technical limitations imposed by the relative low sensitivity of the A2AR antibodies, this change in A1R/A2AR stoichiometry indicates that it should lead to a decrease in the population of A2ARs forming heteromers with A1Rs in those glutamatergic terminals [17]
Summary
Restless legs syndrome (RLS) is a common sensorimotor disorder, whose basic components include a primary sensory experience, akathisia (an urgent need to move), and in about 80% of patients a secondary motor component, periodic leg movements during sleep (PLMS), can be found [1,2]. BID in rodents recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype [3,4]. These neurochemical changes include presynaptic hyperdopaminergic and hyperglutamatergic states [2,3,4]. Utilization of the BID-rodent model of RLS could allow the identification of new neurochemical pathways and changes not previously reported in the human condition. Alterations in the adenosinergic system found in the BID rodent model [3,5] was an important new translational finding that led to a new potential treatment for RLS [6,7]
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