# Postsynaptic functions of neuronal adhesion molecules: focus on Cntnap2

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $489,269

## Abstract

PROJECT SUMMARY
Neurodevelopmental psychiatric disorders including intellectual disability (ID), autism (ASD) and schizophrenia (SZ) are
often comorbid with neurological disorders, such as epilepsy. However, the biological substrates of such comorbidity are
poorly understood. Understanding these molecular substrates could provide insight into the pathogenesis of these
disorders as well as into fundamental neurobiological processes. One promising strategy is to investigate inherited,
monogenic neurodevelopmental syndromes comorbid with epilepsy. Mutations in a number of genes have recently been
discovered which cause neurodevelopmental disorders comorbid with epilepsy. Interestingly, the majority of such genes
have putative functions at synapses and in dendrites, prompting the hypothesis that synaptic connectivity dysfunctions
could be key for both types of disorders. Notably, mutations in a disproportionately large number of synaptic adhesion
molecules are associated with neuropsychiatric disorders, underscoring the importance of understanding their neuronal
functions. A significant fraction of these genes encode members of the neurexin and contactin family. Here we propose to
investigate the synaptic and dendritic functions of a prominent representative of this family, CNTNAP2, mutations in
which cause monogenic syndromes of ID, ASD, and SZ comorbid with epilepsy. Because Cntnap2 modulates synapse
structure and function, here we propose to investigate novel molecular mechanism underlying Cntnap2 functions newly
discovered by us, such as glutamate receptor trafficking, interneuron dendrite arborization, and paracrine signaling by
ectodomain shedding. Based on our preliminary studies we hypothesize that Cntnap2 plays crucial roles in AMPAR
trafficking and in the maintenance of synapto-dendritic architecture through its protein interaction network. We will test
this hypothesis by employing several novel and cutting-edge methodologies such as superresolution and multi-photon
imaging, LC-MS/MS proteomics, and CRISPR/Cas9-engineered iPSC-derived neurons (iN), and by integrating
mechanistic studies in neuronal cultures with human iNs and mouse models. We will pursue the following Specific Aims:
1) Regulation of AMPAR trafficking by Cntnap2 and its protein partners; 2) Control of spine architecture and interneuron
dendrite arborization by Cntnap2 and its partners; 3) Mechanisms of paracrine signaling by Cntnap2 extracellular domain
shedding. Data generated will provide novel insight into signaling by Cntnap2, the regulation of synaptic circuits in the
brain shedding new light on glutamate receptor trafficking by adhesion molecules, formation of neurotransmitter receptor
intracellular aggregates, nanoscopic localization of synaptodendritic molecules, interneuron-specific maintenance of
dendritic arborization, control of cortical E/I balance, as well as paracrine signaling by ectodomain shedding. Proposed
studies will also uncover mechanisms potentially r...

## Key facts

- **NIH application ID:** 9957138
- **Project number:** 5R01NS100785-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peter Penzes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,269
- **Award type:** 5
- **Project period:** 2017-07-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957138

## Citation

> US National Institutes of Health, RePORTER application 9957138, Postsynaptic functions of neuronal adhesion molecules: focus on Cntnap2 (5R01NS100785-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9957138. Licensed CC0.

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