title: Diabetic hyperglycemia reduces Ca2+ permeability of extrasynaptic AMPA receptors in AII amacrine cells.
abstract: There is increasing evidence that diabetic retinopathy is a primary neuropathological disorder that precedes the microvascular pathology associated with later stages of the disease. Recently, we found evidence for altered functional properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in A17, but not AII, amacrine cells in the mammalian retina, and the observed changes were consistent with an upregulation of the GluA2 subunit, a key determinant of functional properties of AMPA receptors, including Ca(2+) permeability and current-voltage (I-V) rectification properties. Here, we have investigated functional changes of extrasynaptic AMPA receptors in AII amacrine cells evoked by diabetes. With patch-clamp recording of nucleated patches from retinal slices, we measured Ca(2+) permeability and I-V rectification in rats with ∼3 wk of streptozotocin-induced diabetes and age-matched, noninjected controls. Under bi-ionic conditions (extracellular Ca(2+) concentration = 30 mM, intracellular Cs(+) concentration = 171 mM), the reversal potential (Erev) of AMPA-evoked currents indicated a significant reduction of Ca(2+) permeability in diabetic animals [Erev = -17.7 mV, relative permeability of Ca(2+) compared with Cs(+) (PCa/PCs) = 1.39] compared with normal animals (Erev = -7.7 mV, PCa/PCs = 2.35). Insulin treatment prevented the reduction of Ca(2+) permeability. I-V rectification was examined by calculating a rectification index (RI) as the ratio of the AMPA-evoked conductance at +40 and -60 mV. The degree of inward rectification in patches from diabetic animals (RI = 0.48) was significantly reduced compared with that in normal animals (RI = 0.30). These results suggest that diabetes evokes a change in the functional properties of extrasynaptic AMPA receptors of AII amacrine cells. These changes could be representative for extrasynaptic AMPA receptors elsewhere in AII amacrine cells and suggest that synaptic and extrasynaptic AMPA receptors are differentially regulated.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal;
authors.forename: Áurea
authors.initials: Á
authors.lastname: Castilho
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway;
authors.forename: Eirik
authors.initials: E
authors.lastname: Madsen
authors.affiliation: Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology, Institute of Biomedical Imaging and Life Sciences (CNC.IBILI) Consortium, University of Coimbra, Coimbra, Portugal; and Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal.
authors.forename: António F
authors.initials: AF
authors.lastname: Ambrósio
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway;
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Veruki
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; espen.hartveit@biomed.uib.no.
authors.forename: Espen
authors.initials: E
authors.lastname: Hartveit
mesh_terms: D000200:Action Potentials; D025042:Amacrine Cells / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D005260:Female; D006943:Hyperglycemia / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology
chemical_list: D018091:Receptors, AMPA; D002118:Calcium
keywords: amacrine cells; calcium-permeable AMPA receptors; diabetes; retina