# Investigating the Mechanism of Optic Nerve disorders associated with Down Syndrome

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $1,475,141

## Abstract

PROJECT ABSTRACT
The prevalence of optic nerve hypoplasia (ONH) among individuals with Down syndrome (DS) is more than ~100
folds higher than in the general population. ONH is characterized by a thin, underdeveloped optic nerve that
often results from secondary loss of retinal ganglion cells (RGCs) and is the leading cause of childhood legal
blindness in developed nations. We have developed a murine model of ONH by manipulating the CASK
(calcium/calmodulin dependent serine protein kinase) gene. The ONH pathology of CASK mutant mice
recapitulates many aspects of human ONH, including the timing of the onset of pathology (after RGC
development, i.e., secondary loss) and the non-progressive nature of the pathology. In addition to ONH, DS and
pathology associated with CASK mutation share other similarities such as microcephaly. Biochemical
experiments suggest that similar to DS, CASK mutation alters mitochondrial function, resulting in aberrant fatty
acid metabolism. We have uncovered a deficiency of the ω-6 polyunsaturated fatty acid arachidonic acid (ARA)
in the central nervous system (CNS) of CASK mutant mice. A specific reduction of ARA-containing lipids has
been also reported in postmortem human DS brains. In both CASK mutant mice and the DS murine model visual
contrast sensitivity is reduced. Based on the literature and our observations, we hypothesize that ARA
deficiency in the optic nerve (ON) leads to ONH in DS. If this hypothesis is correct, dietary ARA
supplementation could ameliorate ONH in DS. In this proposal, we plan to use two independent murine DS
models (Ts65Dn and DP16 mice) to investigate retinal circuit and retinogeniculate connectivity using appropriate
markers and tracers along with imaging techniques. Three-dimensional ultrastructural morphometry of the ON
in DS murine models will be performed using serial block-face scanning electron microscopy (SBFSEM).
Behavioral experiments will document visual defects. Visual circuit function will be evaluated with a novel in vivo
electrophysiological technique we have named Network Response to Visual Excitation (NeRVE), a method that
will be applicable beyond this proposal to better understand rodent vision processing. Mitochondrial metabolism,
reactive oxygen species generation, oxidative damage, and fatty acid metabolic defects in the retina, optic nerve
and brain of two independent DS mouse models will be measured. We will also quantify the levels of two ω-
polyunsaturated fatty acids (docosahexaenoic acid and ARA), as well as phospholipids, in the ON of both types
of DS mice. Finally, we will test if ARA supplementation ameliorates known defects in visual acuity and contrast
sensitivity in these two DS mouse models. Our study is likely to provide data on DS pathobiology and provide a
clear mechanism for the co-occurrence of ONH in DS. Furthermore, promising results from our ARA
supplementation study would be immediately translatable into clinical practice for the amelioration of ONH i...

## Key facts

- **NIH application ID:** 11074234
- **Project number:** 7R01EY033141-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Konark Mukherjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,475,141
- **Award type:** 7
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11074234

## Citation

> US National Institutes of Health, RePORTER application 11074234, Investigating the Mechanism of Optic Nerve disorders associated with Down Syndrome (7R01EY033141-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11074234. Licensed CC0.

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