Loss of Synaptic Connectivity, Particularly in Second Order Neurons Is a Key Feature of Diabetic Retinal Neuropathy in the Ins2Akita Mouse

Abstract

Retinal neurodegeneration is a key component of diabetic retinopathy (DR), although the detailed neuronal damage remains ill-defined. Recent evidence suggests that in addition to amacrine and ganglion cell, diabetes may also impact on other retinal neurons. In this study, we examined retinal degenerative changes in Ins2Akita diabetic mice. In scotopic electroretinograms (ERG), b-wave and oscillatory potentials were severely impaired in 9-month old Ins2Akita mice. Despite no obvious pathology in fundoscopic examination, optical coherence tomography (OCT) revealed a progressive thinning of the retina from 3 months onwards. Cone but not rod photoreceptor loss was observed in 3-month-old diabetic mice. Severe impairment of synaptic connectivity at the outer plexiform layer (OPL) was detected in 9-month old Ins2Akita mice. Specifically, photoreceptor presynaptic ribbons were reduced by 25% and postsynaptic boutons by 70%, although the density of horizontal, rod- and cone-bipolar cells remained similar to non-diabetic controls. Significant reductions in GABAergic and glycinergic amacrine cells and Brn3a+ retinal ganglion cells were also observed in 9-month old Ins2Akita mice. In conclusion, the Ins2Akita mouse develops cone photoreceptor degeneration and the impairment of synaptic connectivity at the OPL, predominately resulting from the loss of postsynaptic terminal boutons. Our findings suggest that the Ins2Akita mouse is a good model to study diabetic retinal neuropathy.

Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

“…Clinicians-in-training are not made aware of RDN as a pathologic process resulting from DM (30), although the entity is well recognized in diabetic animal and human studies (1,3,27,31,32). One reason is that any changes in the diabetic retina are almost always attributed to the frequently recognized microvascular alterations culminating in ischemia of the retina and subsequent up-regulation of cytokines such as vascular endothelial growth factor (8,(33)(34)(35)(36)(37).…”

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

“…Intriguingly, disruption of insulin receptor signaling in cone photoreceptors causes disorganized and reduced photoreceptor ribbon synapses (79), similar to the types observed in RBP4-Tg mice. Likewise, insulin-deficient diabetic mice also develop a progressive loss of photoreceptor ribbon synapses (84) and decreased expression of presynaptic proteins (85). Since an elevation of RBP4 levels can inhibit insulin receptor signaling in adipose tissue, it is plausible that an elevation of RBP4 levels could similarly disrupt insulin receptor signaling in the retina as an underlying mechanism contributing to neuronal dysfunction and degeneration in RBP4-Tg mice, and this should be a subject for future investigation.…”

<b>Spatio-temporal Effects of Standardized Palpation on Referred Sensations and Pain from the Masseter Muscle in Healthy Individuals </b>

“…Local pain is defined as pain located to the source of pain, referred pain is defined as pain felt in a different region or structure away from the source of pain (2). Although several studies have proposed mechanisms for referred pain (3)(4)(5), the actual processes underlying referred pain in the orofacial area have yet to be clarified. Despite this the extensive convergence of afferent input from various tissues onto wide-dynamic range neurons and central sensitization is believed to be crucially involved (6).…”