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Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the Nf1 tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.

Hereditary retinal degenerations result from varied pathophysiologic mechanisms, all ultimately characterized by photoreceptor dysfunction and death. Hence, much research on these diseases has concentrated on the outer retina. Over the past decade or so increasing attention has focused on concomitant changes in complex inner retinal neural circuits that process visual signals for transmission to the brain. One striking abnormality develops before the ultimately profound anatomic disruption of the inner retina. Highly elevated spontaneous activity was first demonstrated in central nervous system visual centers in vivo by Dräger and Hubel (1978), and subsequently has been confirmed in vitro, now in multiple animal models and by multiple investigators (see other contributions to this Research Topic). What evidence exists that this phenomenon occurs in human patients with retinal degeneration, and what is the ultimate effect of spontaneous hyperactivity in the output neurons, the retinal ganglion cells? Here I summarize abnormalities of visual perception among patients with retinal degeneration that may arise from hyperactivity. Next, I consider the disruption of neural encoding and anatomic connectivity that may result within the retina and in downstream visual centers of the brain. I then consider how specific characteristics of hyperactivity may distinguish various forms or stages of retinal degeneration, potentially helping in the near future to refine diagnosis and/or treatment choices for different patients. Finally, I review how consideration of these features may help optimize pharmacologic, gene, stem cell, prosthetic or other therapies to forestall visual loss or restore sight.

Complex alterations in the anatomy of outer retinal pathways accompany photoreceptor degeneration in the rd1 mouse model of retinitis pigmentosa, whereas inner retinal neurons appear relatively preserved. However, the progressive loss of photoreceptor input likely alters the neural circuitry of the inner retina. This study investigated resulting changes in the activity of surviving ganglion cells. Multielectrode recording monitored spontaneous and light-evoked extracellular action potentials simultaneously from 30 to 90 retinal ganglion cells of wild-type (wt) or rd1 mice. In rd1 mice, this activity evolves through three phases. First, normal spontaneous "waves" of correlated firing are seen at postnatal day 7 (P7) and last until shortly after eye opening. Second, at P14, full-field light flashes evoke reliable responses in many cells, with preferential preservation of OFF responses. These diminish as photoreceptor degeneration progresses. Third, once light-evoked responses have disappeared in early adulthood, surviving rd1 ganglion cells fire at a much higher spontaneous frequency than normal, sometimes in rhythmic bursts that are distinct from the developmental "waves." This hyperactivity is sustained well into adulthood, for weeks after photoreceptors have disappeared. Thus striking alterations occur in inner retinal physiology as retinal degeneration progresses in the rd1 mouse. Blindness occurs in the face of sustained hyperactivity among ganglion cells, which remain viable for months despite this activity. ON and OFF responses are differentially affected in early stages of degeneration. While the source of these changes remains to be learned, such features should be considered in designing more effective treatments for these disorders. [ABSTRACT FROM AUTHOR]