Molecular and physiological mechanisms of inner retinal remodeling - PROJECT SUMMARY Retinal degeneration results in low vision and blindness by causing primary death of rods and cones and secondary pathophysiological remodeling of inner retinal neurons. During remodeling, the retinal ganglion cells (RGCs) -the only information output channel of the retina- become intrinsically hyperactive, decreasing the signal-to-noise (SNR) ratio of remaining light responses (mid-degeneration), and of vision restoration methodologies such as optogenetics (after degeneration). Together with layer-specific changes in gene expression throughout the inner retina and reorganization of synaptic connections, remodeling is predicted to dramatically affect the receptive fields and, therefore, corrupt the retinal circuits that are responsible for at least 40 known signal computations of visual information. However, elucidation of the mechanisms behind genetic, morphological, and physiologically-driven circuit corruption is almost impossible without first identifying and manipulating the root cause behind RGC remodeling. We have shown that upregulation and hyperactivation of the retinoic acid receptor (RAR) is necessary and sufficient for degeneration-dependent spontaneous hyperactivity. Inhibition of RAR -without rescuing the death of photoreceptors- results in decreased hyperactivity, decompressed SNR, and improved contrast sensitivity and visual acuity in vivo. This not only highlights the medical significance of this discovery, but also demonstrates that inner retinal computations are essential for proper image-forming visual functionality. In this proposal, we seek to leverage this fundamental breakthrough and our own expertise in the field to dissect the genetic, morphological and physiological events that lead from RAR activation to neuronal remodeling, with the goal of mapping out the extent of circuit corruption in distinct RGC populations, and to understand how these changes in the retina affect key postsynaptic target areas of the downstream visual pathway. Preliminary data show that RAR’s downstream target in Off-RGCs, the purinergic 2x isoform 7 receptor (P2X7), known to cause membrane hyperpermeability in a RAR-dependent manner, is also necessary and sufficient to cause spontaneous and intrinsic neuronal hyperactivity. However, the mechanisms that mediate between RAR upregulation and downstream activation of P2X7, and the interaction between them and neuronal hyperexcitability, are unknown. We propose to study the consequences of degeneration-dependent upregulation of the RAR-P2X7 signaling pathway in RGCs by employing advanced methodologies and innovative technologies, pioneered by our lab and our collaborators. Our expected results will aim to define crucial components in current and future strategies for visual improvement and vision restoration in patients with photoreceptor dystrophies, such as preventing or reversing retinal remodeling concomitantly with treatments aimed at slowing down the progression of degeneration or restoring light responses. Beyond vision impairment, our results will tackle essential questions regarding the mechanisms responsible for the extent and limitations of neuronal plasticity in sensory systems.
