ON-Type Retinal Ganglion Cells are Preferentially Affected in STZ-Induced Diabetic Mice

Abstract

PURPOSE. We investigate morphologic and physiologic alterations of ganglion cells (GCs) in a streptozocin (STZ)-induced diabetic mouse model. METHODS. Experiments were conducted in flat-mount retinas of mice 3 months after the induction of diabetes. Changes in morphology of four subtypes of GCs (ON-type RGA2 [ON-RGA2], OFF-type RGA2 [OFF-RGA2], ON-type RGC1 [ON-RGC1], and ON-OFF type RGD2 [ON-OFF RGD2]) were characterized in Thy1-YFP transgenic mice. Using whole-cell patchclamp recording, passive membrane properties and action potential (AP) firing properties were further investigated in transient ON-and OFF-RGA2 cells. RESULTS. Morphologic parameters were significantly altered in the dendrites branching in the ON sublamina of the inner plexiform layer (IPL) for ON-RGA2 cells and ON-OFF RGD2 cells. Much less significant changes, if any, were seen in those arborizing in the OFF sublamina of the IPL for OFF-RGA2 and ON-OFF RGD2 cells. No detectable changes in morphology were seen in RGC1 cells. Electrophysiologically, increased resting membrane potentials and decreased membrane capacitance were found in transient ON-RGA2 cells, but not in transient OFF-RGA2 cells. Similar alterations in AP firing properties, such as an increase in AP width and reduction in maximum spiking rate, were shared by these two subtypes. Furthermore, in response to depolarizing current injections, both cells generated more APs suggesting an enhanced excitability of these cells in diabetic conditions. CONCLUSIONS. These differential changes in morphology and electrophysiology in subtypes of GCs may be responsible for reduced contrast sensitivity known to occur during the early stage of diabetic retinopathy.

Early diabetes impairs ON sustained ganglion cell light responses and adaptation without cell death or dopamine insensitivity

“…This demonstrates that at least one channel of retinal output to the lateral geniculate nucleus may be dysfunctional at this early stage of diabetes. This finding is supported by previous work reporting hyper-excitability of background activity of dark-adapted ON ganglion cell after 12 weeks of diabetes, due to increased spontaneous spiking, changes in passive membrane properties and voltage-gated conductances (Cui et al, 2019;Yu et al, 2013).…”

“…10, Table 6) the ganglion cell changes were accompanied by significant ganglion cell death (16.4% of those under consideration) that could trigger expansion of the remaining ganglion cell dendrites. Additionally, a different study showed a decreased in dendritic area in a subtype of ON ganglion cells without cell loss (Cui et al, 2019) after 12 weeks of diabetes, suggesting dendritic expansion is unlikely in our sample. Alternatively, there is some evidence for early diabetic changes in glutamate receptor subunit composition and glutamate transporter expression in the retina (Castilho et al, 2015a;Castilho et al, 2015b;Lau et al, 2013;Santiago et al, 2009;Santiago et al, 2008) that could potentially lead to increased inputs to ganglion cells.…”

“…We examined these phenomena in the context of the rod pathway, as current evidence points to its disruption in early diabetes (Aung et al, 2014;Castilho et al, 2015a;Moore-Dotson et al, 2016;Moore-Dotson and Eggers, 2019;Pardue et al, 2014). Previous work from our lab has shown that rod bipolar cells in diabetic mice receive less evoked inhibition than those in control animals (Moore-Dotson et al, 2016;Moore-Dotson and Eggers, 2019), which could explain the hyper-excitability of ON ganglion cells that has been reported in an animal model of early diabetes (Cui et al, 2019;Yu et al, 2013). In the wild-type retina, this inhibition is controlled by the activation of dopamine type-1 receptors (D1Rs) located on amacrine cells (Flood et al, 2018).…”

Relationship Between Estimated Glucose Disposal Rate and Type 2 Diabetic Retinopathy

“…52,53 Subsequent microthrombi development, cell adhesion molecules, leukostasis, and cytokine activation are linked to the weakening of retinal ganglion cells and nerve fiber layers. [54][55][56] In the current study, it was found that the link between eGDR and DR was stronger in women than in men, and that eGDR was associated with proliferative DR in women only among T2DM patients. The results of our study demonstrated that female sex was another independent risk factor for DR. A growing body of research has shown a link between sex and the risk of DR in T2DM.…”

The effects of early diabetes on inner retinal neurons

“…These changes were suggested to be due to changes in synaptic inputs, potentially due to reduced inhibitory inputs onto bipolar cells. Additionally, after 12 weeks of diabetes, ON ganglion cells show increased excitability (Cui et al, 2019) that could potentially increase their response to glutamatergic inputs.…”