Midbrain pathways for visual hypersensitivity in neurofibromatosis type 1

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PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1 in 3500 individuals worldwide due to inactivating mutations in the NF1 gene. Cognitive symptoms in NF1 include impaired executive functioning, autistic features, speech and language delays, attention deficits, hyperactivity, and impulsivity. Disease manifestations are due to reduced expression of functional neurofibromin, the protein product of NF1 that inhibits Ras-MAPK (Ras-Raf-MEK-ERK) signaling cascades by accelerating Ras-GTP hydrolysis. Using a heterozygous knockout (Nf1+/-) mouse model of NF1, we previously discovered that Nf1 haploinsufficiency causes hypersensitivity to salient visual stimuli, such as a looming disc that promotes rapid escape to an available shelter by simulating predator approach from above. These phenotypes are likely controlled by the superior colliculus (SC), which receives direct visual input from retinal ganglion cells (RGCs) and coordinates behavioral responses to looming visual threats. Recently, it has been shown that cultured Nf1+/- RGCs are more excitable in vitro. These results raise the possibility that Nf1 haploinsufficiency enhances the sensitivity of SC-projecting RGCs to light; however, no study to date has examined RGC firing in an intact Nf1+/- retina or recorded neuronal responses in the superior colliculus in Nf1+/- mice. In this proposal we will test the hypothesis that a MAPK-dependent increase in the sensitivity of Nf1+/- RGCs to light produces visual hypersensitivity phenotypes via the downstream superior colliculus. In Aim 1, we will directly measure RGC responses to visual stimuli ex vivo and in vivo in NF1 model mice. In Aim 2, we will use calcium imaging and optogenetics to define the contribution of ventral SC glutamatergic neurons to phenotypic expression. Finally, in Specific Aim 3, we will test the role of activated MAPK signaling in NF1-associated phenotypes by determining if visual hypersensitivity is recapitulated in a novel knock-in mouse model of Noonan syndrome. If successful, these experiments will identify a new role for retinotectal visual processing circuits in NF1 and may paradigmatically shift how attentional and visuospatial deficits are conceptualized in this disease.