title: Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus.
abstract: Diabetes leads to dysfunction of the neural retina before and independent of classical microvascular diabetic retinopathy, but previous studies have failed to demonstrate which neurons and circuits are affected at the earliest stages. Here, using patch-clamp recording and two-photon Ca(2+) imaging in rat retinal slices, we investigated diabetes-evoked changes in a microcircuit consisting of rod bipolar cells and their dyad postsynaptic targets, AII and A17 amacrine cells, which play an essential role in processing scotopic visual signals. AII amacrines forward their signals to ON- and OFF-cone bipolar cells and A17 amacrines provide GABAergic feedback inhibition to rod bipolar cells. Whereas Ca(2+)-permeable AMPA receptors mediate input from rod bipolar cells to both AII and A17 amacrines, diabetes changes the synaptic receptors on A17, but not AII amacrine cells. This was expressed as a change in pharmacological properties and single-channel conductance of the synaptic receptors, consistent with an upregulation of the AMPA receptor GluA2 subunit and reduced Ca(2+) permeability. In addition, two-photon imaging revealed reduced agonist-evoked influx of Ca(2+) in dendritic varicosities of A17 amacrine cells from diabetic compared with normal animals. Because Ca(2+)-permeable receptors in A17 amacrine cells mediate synaptic release of GABA, the reduced Ca(2+) permeability of these receptors in diabetic animals leads to reduced release of GABA, followed by disinhibition and increased release of glutamate from rod bipolar cells. This perturbation of neuron and microcircuit dynamics can explain the decreased dynamic range and sensitivity of scotopic vision that has been observed in diabetes.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen N-5009, Norway, Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3000-548, and.
authors.forename: Áurea
authors.initials: Á
authors.lastname: Castilho
authors.affiliation: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3000-548, and Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal 3000-548.
authors.forename: António F
authors.identifier: http://orcid.org/0000-0002-0477-1641
authors.initials: AF
authors.lastname: Ambrósio
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen N-5009, Norway, margaret.veruki@biomed.uib.no espen.hartveit@biomed.uib.no.
authors.forename: Espen
authors.initials: E
authors.lastname: Hartveit
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen N-5009, Norway, margaret.veruki@biomed.uib.no espen.hartveit@biomed.uib.no.
authors.forename: Margaret L
authors.identifier: http://orcid.org/0000-0002-0532-144X
authors.initials: ML
authors.lastname: Veruki
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D025042:Amacrine Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D009434:Neural Pathways / Q000473:pathology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D051245:Retinal Bipolar Cells / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C110702:IEM 1460; D018091:Receptors, AMPA; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C104722:glutamate receptor ionotropic, AMPA 2; D000218:Adamantane; D002118:Calcium
keywords: amacrine cells; calcium-permeable AMPA receptors; diabetes; retina
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