# Neuronal excitability and copy number variation disorders

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $638,048

## Abstract

ABSTRACT
Copy number variations (CNVs) are a major cause of neurodevelopmental disorders, but their biological
investigation and pharmacological targeting pose many challenges. Deletions
locus are
among
the
most
frequent
causes
of
autism
spectrum
disorder
and duplications at the 16p11.2
(ASD). However, alterations in the
corresponding protein networks, especially at key cellular sites for pathogenesis, have not been investigated in
this or other CNVs. We propose to use compartment-specific neuroproteomics, combined with bioinformatics,
super-resolution microscopy, and drug repurposing, to understand and alter dendritic excitability phenotypes
in 16p11.2 mouse and induced pluripotent stem cell (iPSC) models. Based on our extensive preliminary data,
we hypothesize that altered expression of PRRT2, which likely regulates the trafficking of a subset of ion
channels and receptors, drives and abnormal complement of ion channels and receptor on the plasma
membrane, leading to abnormal excitability, excitatory/inhibitory (E/I) balance, and network properties in
16p11.2 models and patients. These phenotypes may be reversed by targeting ion channel function using FDA-
approved anti-epileptic drugs or ERK signaling using repurposed cancer drugs. Our collaborative team, which
includes experts in neurodevelopmental disorders (Penzes), neuroproteomics (Savas), molecular pharmacology
(Barbolina), and ion channel physiology (George) will employ a powerful and multidisciplinary combination of
highly innovative methodologies to pursue the following Specific Aims: (1) To chart the developmental
regulation and determine molecular mechanisms underlying abnormal excitability in dup and del mice and
human neurons. (2) To chart the developmental profile and determine the molecular mechanisms underlying
the role of PRRT2 as a driver of excitability and seizure phenotypes. (3) Pharmacological reversal of 16p11.2 del
and dup phenotypes. This proposal will be the first to demonstrate that cellular subcompartment-specific
proteomics combined with super-resolution microscopy, informed by highly penetrant monogenic disease
genes within a CNV, can identify novel disease mechanisms. Such phenotypes could be reversed globally by
targeting network hubs using repurposed drugs, opening novel strategies for the treatment of
neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10250497
- **Project number:** 5R01NS114977-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peter Penzes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $638,048
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250497

## Citation

> US National Institutes of Health, RePORTER application 10250497, Neuronal excitability and copy number variation disorders (5R01NS114977-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10250497. Licensed CC0.

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