# Adhesion molecules and developmental epilepsy disorders

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2022 · $544,893

## Abstract

PROJECT SUMMARY
This is a renewal application for a grant aimed to understand abnormal brain development and function in
neurodevelopmental disorders co-morbid with epilepsy, and to explore preclinical rescue strategies with the potential
of to reverse these abnormalities. Neurodevelopmental disorders, such as intellectual disability and autism are often
comorbid with seizure disorders, such as epilepsy. Mutations in a number of genes have recently been discovered
which cause neurodevelopmental disorders comorbid with epilepsy, suggesting common etiological mechanisms.
Among these, genes encoding neuronal adhesion molecules are very highly represented. Here we propose to
continue to investigate novel neuronal functions of a prominent representative of this family, CNTNAP2, mutations in
which cause monogenic syndromes of intellectual disability, autism, and language disorder, comorbid with epilepsy.
Specifically, we will investigate the neurodevelopmental functions of CNTNAP2 ectodomain shedding (cleavage and
release of the extracellular domain) in paracrine signaling. Based on our findings from the previous funding period,
we hypothesize that specific regions on CNTNAP2's ectodomain can modulate network properties and seizure
activity in the intact mouse brain; CNTNAP2-ecto shedding is dysregulated in human subjects with and mouse models
of neurodevelopmental seizure disorders. We will test this hypothesis by combining expertise in molecular
neurobiology, epilepsy, proteomics, and pharmacology, using animal models and human clinical CSF samples, and
by employing several cutting-edge methodologies, in the following Specific Aims: 1) To map the structural
determinants of CNTNAP2-ecto function. 2) To characterize the impact of CNTNAP2-ecto on network and seizure
activity in mice. 3) To explore the relationship between shed ectodomains detected in the CSF and seizure activity.
On a basic level, data generated will provide new insights into the biology of paracrine signaling by neuronal
ectodomain shedding and reveal novel mechanisms of regulation neuronal network activity during brain development.
In the long run, our studies will provide novel insight into the molecular basis of alterations in both epilepsy and
neurodevelopmental disorders and have the potential to provide preclinical proof-of-principle for novel therapeutic
strategies for interventions in developmental seizure disorders.

## Key facts

- **NIH application ID:** 10592736
- **Project number:** 2R56NS100785-05A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peter Penzes
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $544,893
- **Award type:** 2
- **Project period:** 2017-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592736

## Citation

> US National Institutes of Health, RePORTER application 10592736, Adhesion molecules and developmental epilepsy disorders (2R56NS100785-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10592736. Licensed CC0.

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