# Cellular and molecular mechanisms underlying the function of SRGAP2 during synaptic development

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $619,879

## Abstract

ABSTRACT
During development, tightly regulated mechanisms establish the proper balance between excitatory (E) and
inhibitory (I) synaptic inputs made onto each neuronal cell type. Several neurodevelopmental disorders are
thought to have emerged from E/I synaptic imbalance including autism spectrum disorders (ASD) and
schizophrenia. However, the mechanisms coordinating excitatory and inhibitory synaptic development are still
poorly understood. We recently discovered that SRGAP2 is a postsynaptic protein playing key roles in vivo in
promoting the rate of excitatory and inhibitory synapses maturation and limiting the density of both types of
synapses made onto pyramidal neurons in the developing cortex. In the previous funding period, we first made
significant progress in dissecting the molecular mechanisms underlying SRGAP2 function at both excitatory
and inhibitory synapses, discovering that its ability to promote excitatory synaptic maturation requires its ability
to bind to Homer1, a key postsynaptic scaffolding protein at excitatory synapses, but promotes inhibitory
synapse maturation through its ability to bind to Gephyrin, a key scaffolding protein at inhibitory synapses.
Finally, SRGAP2 regulates the density of excitatory and inhibitory synapses made onto a pyramidal neuron
through its Rac1-GAP activity.
Secondly, we and others discovered that SRGAP2 has undergone several partial gene duplications specifically
in the human lineage. Only one of these gene duplications, called SRGAP2C (the ancestral copy of the human
gene was renamed SRGAP2A) has been fixed in the human population and is expressed in the developing
human brain. We discovered that SRGAP2C binds to and inhibits the functions of SRGAP2A during synaptic
development. When human-specific SRGAP2C is expressed in mouse cortical pyramidal neurons in vivo, it
induces significant delay (neoteny) of synaptic maturation and significant increase in both excitatory and
inhibitory synapse density.
The present proposal constitutes a comprehensive, multi-disciplinary approach to address some fundamental
questions raised by our results from the previous funding period: Is SRGAP2A and its human-specific
paralogs only involved in synaptic development or is it also regulating synaptic plasticity? What types
of functional properties emerge in mouse cortical circuits following humanization of SRGAP2C
expression? What are the consequences of structural changes induced by SRGAP2A and its human-
specific paralog SRGAP2C on cortical circuit organization and function as well as behavioral
performance? Our aim is to test if human-specific gene duplication of SRGAP2A that led to the emergence of
SRGAP2C represented an evolutionary relevant substrate for the emergence of new functional properties in
cortical circuits. This project will tackle with unprecedented relevance the relationship between genes,
neural circuits and behavior in a framework of human cortical development and evolution.

## Key facts

- **NIH application ID:** 9938695
- **Project number:** 5R01NS067557-11
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** FRANCK POLLEUX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $619,879
- **Award type:** 5
- **Project period:** 2010-03-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938695

## Citation

> US National Institutes of Health, RePORTER application 9938695, Cellular and molecular mechanisms underlying the function of SRGAP2 during synaptic development (5R01NS067557-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9938695. Licensed CC0.

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