Castilho Á, Madsen E, Ambrósio AF, Veruki ML, Hartveit E. Diabetic hyperglycemia reduces Ca 2ϩ permeability of extrasynaptic AMPA receptors in AII amacrine cells. J Neurophysiol 114: 1545-1553, 2015. First published July 8, 2015 doi:10.1152/jn.00295.2015.-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 ␣-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 2ϩ 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 2ϩ permeability and I-V rectification in rats with ϳ3 wk of streptozotocin-induced diabetes and age-matched, noninjected controls. Under bi-ionic conditions (extracellular Ca 2ϩ concentration ϭ 30 mM, intracellular Cs ϩ concentration ϭ 171 mM), the reversal potential (E rev ) of AMPA-evoked currents indicated a significant reduction of Ca 2ϩ permeability in diabetic animals [E rev ϭ Ϫ17.7 mV, relative permeability of Ca 2ϩ compared with Cs ϩ (P Ca /P Cs ) ϭ 1.39] compared with normal animals (E rev ϭ Ϫ7.7 mV, P Ca /P Cs ϭ 2.35). Insulin treatment prevented the reduction of Ca 2ϩ permeability. I-V rectification was examined by calculating a rectification index (RI) as the ratio of the AMPA-evoked conductance at ϩ40 and Ϫ60 mV. The degree of inward rectification in patches from diabetic animals (RI ϭ 0.48) was significantly reduced compared with that in normal animals (RI ϭ 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.

In chemical synapses, neurotransmitter molecules released from presynaptic vesicles activate populations of postsynaptic receptors that vary in functional properties depending on their subunit composition. Differential expression and localization of specific receptor subunits are thought to play fundamental roles in signal processing, but our understanding of how that expression is adapted to the signal processing in individual synapses and microcircuits is limited. At ribbon synapses, glutamate release is independent of action potentials and characterized by a high and rapidly changing rate of release. Adequately translating such presynaptic signals into postsynaptic electrical signals poses a considerable challenge for the receptor channels in these synapses. Here, we investigated the functional properties of AMPA receptors of AII amacrine cells in rat retina that receive input at spatially segregated ribbon synapses from OFF-cone and rod bipolar cells. Using patch-clamp recording from outside-out patches, we measured the concentration dependence of response amplitude and steady-state desensitization, the single-channel conductance and the maximum open probability. The GluA4 subunit seems critical for the functional properties of AMPA receptors in AII amacrines and immunocytochemical labeling suggested that GluA4 is located at synapses made by both OFF-cone bipolar cells and rod bipolar cells. Finally, we used a series of experimental observables to develop kinetic models for AII amacrine AMPA receptors and subsequently used the models to explore the behavior of the receptors and responses generated by glutamate concentration profiles mimicking those occurring in synapses. These models will facilitate future in silico modeling of synaptic signaling and processing in AII amacrine cells.

Den store imitatorén alene eller én av flere? 1101 Syfilis er ofte blitt omtalt som «den store imitator» fordi sykdommen kan ha mange uspesifikke symptomer. Imidlertid er begrepet i årenes forløp blitt brukt om en rekke ulike sykdommer. Vi foreslår derfor at man ved imitatortilstander heller bruker uttrykket «en stor imitator».

Avdeling for radiologi og nukleaermedisin Oslo universitetssykehus, Ullevål Johan Wang er lege i spesialisering i radiologi. Forfa eren har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter. Thoraxkirurgisk avdeling Oslo universitetssykehus, Ullevål og Institu for klinisk medisin Universitetet i Oslo Peter Majak er ph.d., spesialist i torakskirurgi, overlege og førsteamanuensis. Forfa eren har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter. Thoraxkirurgisk avdeling Oslo universitetssykehus, Ullevål Per Reidar Woldbaek er dr.med., spesialist i torakskirurgi og overlege. Forfa eren har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter. Avdeling for radiologi og nukleaermedisin Oslo universitetssykehus, Ullevål Eirik Madsen er spesialist i radiologi og overlege. Forfa eren har fylt ut ICMJE-skjemaet og oppgir ingen interessekonflikter.