# Midbrain pathways for visual hypersensitivity in neurofibromatosis type 1

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $380,481

## Abstract

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.

## Key facts

- **NIH application ID:** 10883642
- **Project number:** 5R01NS126108-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** John Elliott Robinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,481
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883642

## Citation

> US National Institutes of Health, RePORTER application 10883642, Midbrain pathways for visual hypersensitivity in neurofibromatosis type 1 (5R01NS126108-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883642. Licensed CC0.

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