IntroductionUnderstanding the retina in health and disease is a key issue for neuroscience and neuroengineering applications such as retinal prostheses. During degeneration, the retinal network undergoes complex and multi-stage neuroanatomical alterations, which drastically impact the retinal ganglion cell (RGC) response and are of clinical importance. Here we present a biophysically detailedin silicomodel of the cone pathway in the retina that simulates the network-level response to both light and electrical stimulation.MethodsThe model included 11, 138 cells belonging to nine different cell types (cone photoreceptors, horizontal cells, ON/OFF bipolar cells, ON/OFF amacrine cells, and ON/OFF ganglion cells) confined to a 300 × 300 × 210μm patch of the parafoveal retina. After verifying that the model reproduced seminal findings about the light response of retinal ganglion cells (RGCs), we systematically introduced anatomical and neurophysiological changes (e.g., reduced light sensitivity of photoreceptor, cell death, cell migration) to the network and studied their effect on network activity.ResultsThe model was not only able to reproduce common findings about RGC activity in the degenerated retina, such as hyperactivity and increased electrical thresholds, but also offers testable predictions about the underlying neuroanatomical mechanisms.DiscussionOverall, our findings demonstrate how biophysical changes typified by cone-mediated retinal degeneration may impact retinal responses to light and electrical stimulation. These insights may further our understanding of retinal processing and inform the design of retinal prostheses.