Polymodal Sensory Integration in Retinal Ganglion Cells

Abstract

An animal's ability to perceive the external world is conditioned by its capacity to extract and encode specific features of the visual image. The output of the vertebrate retina is not a simple representation of the 2D visual map generated by photon absorptions in the photoreceptor layer. Rather, spatial, temporal, direction selectivity and color “dimensions” of the original image are distributed in the form of parallel output channels mediated by distinct retinal ganglion cell (RGC) populations. We propose that visual information transmitted to the brain includes additional, light-independent, inputs that reflect the functional states of the retina, anterior eye and the body. These may include the local ion microenvironment, glial metabolism and systemic parameters such as intraocular pressure, temperature and immune activation which act on ion channels that are intrinsic to RGCs. We particularly focus on light-independent mechanical inputs that are associated with physical impact, cell swelling and intraocular pressure as excessive mechanical stimuli lead to the counterintuitive experience of “pressure phosphenes” and/or debilitating blinding disease such as glaucoma and diabetic retinopathy. We point at recently discovered retinal mechanosensitive ion channels as examples through which molecular physiology brings together Greek phenomenology, modern neuroscience and medicine. Thus, RGC output represents a unified picture of the embodied context within which vision takes place.

TRPV4 regulates calcium homeostasis, cytoskeletal remodeling, conventional outflow and intraocular pressure in the mammalian eye

“…Given that IOP reduction represents a highly effective treatment of both hypertensive and normal-tension versions of the disease 1 , the novel prodrug analog described here may provide safe and effective glaucoma therapy by targeting the pressure sensor, a major currently unmet need in the clinical treatment of glaucoma 2 . The potential for protecting RGCs from mechanical stress by TRPV4 inhibition 21 63 offers additional impetus to explore possible solutions for combined IOP-lowering and neuroprotective treatments to prevent vision loss in glaucoma.…”

Cholesterol regulates polymodal sensory transduction in Müller glia

“…Hypercholesterolemic retinas show a striking resemblance to the effects of excessive TRPV4 activation (reactive gliosis, increased permeability of the retinal microvascular endothelial barrier, pathological glial swelling and RGC degeneration) (Jo et al, ; Phuong et al, ; Ryskamp et al, ). Accordingly, PLA2 blockers suppressed both Müller glial TRPV4 activation (Ryskamp et al, ) and the reactive response induced by hypercholesterolemia and diabetes mellitus (Acharya et al, ) whereas cholesterol‐lowering drugs reduced the risk for contracting glaucoma (Marcus et al, ) which might involve TRPV4 overactivation (Križaj, ). Hence, TRPV4 channels could represent an auxiliary target in proinflammatory dyslipidemic pathologies.…”

Polymodal TRPV1 and TRPV4 Sensors Colocalize but Do Not Functionally Interact in a Subpopulation of Mouse Retinal Ganglion Cells

“…RGCs are typically categorized by their light response and serendipitous expression of molecular markers ( Zeng and Sanes, 2017 ) but this ignores the possibility that RGC might also be classified based on their responsiveness to the local milieu, which continually bombards them with mechanical, cardiovascular and immune signals. We know that non-canonical non-synaptic sensory inputs can dramatically impact the function and survival of RGC subtypes ( Muller et al, 2014 ; Duan et al, 2015 ; Križaj, 2016 ; Ou et al, 2016 ) yet the lack of knowledge about the transduction mechanisms that mediate them hampers physiological insight and treatment in diseases such as glaucoma, diabetic retinopathy, ischemia, and traumatic ocular injury.…”