Loss of Retinogeniculate Synaptic Function in the DBA/2J Mouse Model of Glaucoma.

Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN), which is then relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown yet are likely to contribute to vision loss. Here, we used anatomic and physiological approaches to study the structure and function of retinogeniculate (RG) synapses in male and female DBA/2J (D2) mice with inherited glaucoma before and after IOP elevation. D2 mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals while patch-clamp measurements of RG synaptic function showed that synaptic transmission was reduced in 9-month and 12-month D2 mice because of the loss of individual RGC axon inputs. TC neuron dendrites had reduced Sholl complexity at 12 months, suggestive of delayed reorganization following reduced synaptic input. There was no detectable change in RGC density in 11- to 12-month D2 retinas, quantified as the number of ganglion cell layer-residing somata immuno-positive for NeuN and immuno-negative for the amacrine marker choline acetyltransferase (ChAT). Thus, observed synaptic defects appear to precede RGC somatic loss. These findings identify glaucoma-associated and IOP-associated deficits in an important subcortical RGC projection target, shedding light on processes linking IOP to vision loss.

Mechanism for Altered Dark-Adapted Electroretinogram Responses in DBA/2J Mice Includes Pupil Dilation Deficits.

PURPOSE: The DBA/2J (D2) mouse is an established model of pigmentary glaucoma, a type of primary open angle glaucoma. Prior studies have documented defects in flash electroretinogram (ERG) responses in D2 mice, but the origin of those defects is not clear. The purpose of this study was to understand the origin of these A-wave and B-wave changes in D2 ERGs. MATERIALS AND METHODS: To accomplish this, we analyzed the differences between 9-month-old DBA/2J-Gpnmb+ (D2-control) and D2 mouse eyes in relation to ERG responses, intraocular pressure (IOP), outer nuclear layer thickness, and pupil area. RESULTS: D2 scotopic ERGs showed lower A-wave amplitude and longer implicit time as well as a significant rightward shift in the intensity-response curve. D2 IOP increased at approximately seven months of age and had a weak correlation with the ERG A-wave sensitivity. Outer nuclear layer thickness was not significantly different in D2s compared to D2-control retinas. D2 mouse pupils also showed abnormal pupillary shape and no dilation following treatment with tropicamide eye drops. The pupil size moderately correlated with the A-wave sensitivity and this was pharmacologically replicated in C57Bl/6J mice following administration of pilocarpine to constrict the pupils. However, pilocarpine treatment did not affect ERG amplitudes. CONCLUSIONS: These data suggest that the smaller pupil sizes prevented light from reaching the photoreceptors and thus contributed to reduced ERG sensitivity in D2 mice. The reduced ERG A-wave amplitude in D2 mice likely results from dysfunctional photoreceptor responses.

Neuronal and Synaptic Plasticity in the Visual Thalamus in Mouse Models of Glaucoma.

Homeostatic plasticity plays important role in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), the early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes related to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma-the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, when IOP rises. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in 9-month-old D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner. These data suggest that glaucoma-associated changes to neuronal excitability and synaptic inputs in the dLGN might represent a combination of both stabilizing/homeostatic plasticity and pathological dysfunction.