# Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis

> **NIH NIH K08** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $188,028

## Abstract

PROJECT SUMMARY
Most metabolic diseases, including two-thirds of lysosomal storage disorders (LSD) affect the brain. For many,
including Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), it is not known how the biochemical defect induces
central nervous system dysfunction. Studies have focused on cellular-level pathology, with few investigations
of how metabolic defects disrupt functional neuronal circuits. Ultimately, disruption of brain networks leads to
the symptoms, such as seizures and neurocognitive regression, that are devastating to patients.
JNCL results from biallelic mutations in CLN3. How loss of CLN3 protein disrupts neurologic function is
unclear. In preliminary work, I have demonstrated that JNCL mice, like human patients, have abnormal
electroencephalograms, suggesting mice are a suitable model for circuit-level studies. On autopsy, JNCL
brains show neurodegeneration and lysosomal storage accumulation; the hippocampus is especially
vulnerable. In my preliminary voltage-sensitive dye imaging (VSDI) studies of the JNCL mouse hippocampus, I
have found progressive changes in excitability. Also, recent studies of late-stage JNCL show synaptic
dysfunction in the mouse hippocampus. However, in studies of late-stage disease it is impossible to parse
which changes are due to the primary loss of CLN3 protein or secondary to widespread neuropathology.
Gene and/or enzyme replacement therapy is being developed for many LSDs. While this is exciting, moving to
gene-based treatment before we know if replacement will fix the patients is problematic. Where and when to
rescue protein expression is unclear. A major unanswered question is if correction of the biochemical defect
underlying a metabolic disease will rescue the function of neuronal networks and improve symptoms.
My central hypothesis is that in JNCL, hippocampal circuit pathology arises from synaptic dysfunction induced
by loss of CLN3 protein. Because of the development of abnormal network dynamics, a vulnerable window
may exist beyond which correction of single cell biochemistry will not correct functional defects. I will evaluate
this by: 1) defining circuit level pathology using VSDI in two JNCL models; 2) exploring the synaptic and
cellular changes driving network changes, and 3) assessing if rescue of CLN3 expression at different stages of
disease can rescue circuit and synaptic dynamics. This work has important implications for future studies of the
basic science of the CLN3 protein and novel therapies for JNCL.
As an MD/PhD, I am passionate about translating basic science discoveries into new therapies for my patients
with neurometabolic disorders. My mentors Dr. Eric Marsh, a physician-scientist neurogeneticist and
electrophysiologist, and Dr. Beverly Davidson, a lysosomal storage disease expert, have devoted their careers
to this goal. Under their guidance, I will use this 5-year experience to learn to apply my electrophysiology skills
to studies of the brain and to prepare for a ...

## Key facts

- **NIH application ID:** 10248394
- **Project number:** 5K08NS105865-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Rebecca Clare Ahrens-Nicklas
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $188,028
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248394

## Citation

> US National Institutes of Health, RePORTER application 10248394, Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis (5K08NS105865-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10248394. Licensed CC0.

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