Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus.
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.
['Castilho|Áurea|Á|', 'Ambrósio|António F|AF|http://orcid.org/0000-0002-0477-1641', 'Hartveit|Espen|E|', 'Veruki|Margaret L|ML|http://orcid.org/0000-0002-0532-144X']
D000218:Adamantane D025042:Amacrine Cells D000818:Animals D002118:Calcium D003921:Diabetes Mellitus, Experimental D019706:Excitatory Postsynaptic Potentials D005260:Female D018698:Glutamic Acid D009434:Neural Pathways D051381:Rats D018091:Receptors, AMPA D051245:Retinal Bipolar Cells D017948:Retinal Rod Photoreceptor Cells D015854:Up-Regulation D005680:gamma-Aminobutyric Acid
retina diabetes amacrine cells calcium-permeable AMPA receptors