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bioRxiv · 10.64898/2025.12.01.691679

Early Diabetic Ca2+ Handling Impairments in the Rod Bipolar Pathway

Hill, J. T.·Wellington, A. J.·Del Villar, D.·Eggers, E. D.
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Abstract

BackgroundPrevious work showed that electrically-evoked inhibition to Rod Bipolar Cells (RBC) is reduced in a mouse model of early diabetes. It is hypothesized that this is due to impaired Ca2+ handling in the presynaptic amacrine cell, either through increased Ca2+ buffering or decreased influx. To test this hypothesis and develop a mechanism for this effect, a model where direct optogenetic activation of inhibitory amacrine cells that expressed the light-activated channel ChR2 was used to isolate amacrine cell inputs to RBCs. Application of selective Ca2+ channel blockers could then assess potential locations of amacrine Ca2+ disruption. Using whole cell patch clamp electrophysiology, recordings were made from a 6 week diabetic population (DM) and vehicle injected non-DM animals. ResultsRobust GABAC receptor inhibitory currents were recorded from RBCs after ChR2 stimulus that were significantly diminished by the application of nifedipine to block L-type Ca2+ channels in both DM and non-DM conditions. There were significant differences in the peak amplitude of these responses between DM and non-DM groups (p = 0.0146). However, in the non-DM group the decay tau of the response to the 50ms stimulus was significantly diminished by nifedipine ({tau} p =0.0498, n = 5), but this was not seen in the DM group ({tau} p = 0.9498, n=7). A 1s nifedipine-reduced response saw its decay tau increase in the DM group but not the non-DM. Ca2+ - induced Ca2+ release (CICR) blockade with ryanodine decreased responsivity equally between groups in the 1s stimulus but showed no significant kinetic changes. CICR blockade for a 50ms stimulus response showed significant kinetic changes in diabetes but otherwise reduced the response equally between DM and non-DM. Blockade of the mitochondrial Ca2+ uniporter (MCU) had little effect on the optogenetic response. ConclusionThis study presents evidence that diabetes alters amacrine cell output to the RBC unmasked through blockade of the L-type calcium channel, and the Endoplasmic Reticulum (ER). An apparent explanation for our results is that DM calcium buffering is dysregulated, leading to prolonged responses. The underlying mechanism for this alteration is complex and not yet clearly elucidated.

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Hill, J. T., Wellington, A. J., Del Villar, D., Eggers, E. D.. 2025-12-03. Early Diabetic Ca2+ Handling Impairments in the Rod Bipolar Pathway. https://doi.org/10.64898/2025.12.01.691679

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