# AMPA receptor trafficking regulates social behaviors in autism

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $408,750

## Abstract

Abstract
Autism spectrum disorders are clinically and genetically heterogeneous. Identification of convergent molecular
pathways and neural circuits underlying autism endophenotypes are crucial to discovery of novel drug targets
for development of effective therapies. Glutamate mediates the majority of excitatory neurotransmission in the
CNS. Glutamate receptor interacting proteins 1/2 (GRIP1/2) are neuron-enriched scaffolding proteins with 7
PDZ domains. PDZ domains 4-6 of GRIP1/2 bind the c-terminal domain of AMPA receptor 2/3 (GluA2/3). Loss
of Grip1/2 expression in mice results in delayed recycling of GluA2 in neurons and increased sociability and
social interactions. Studies of AMPA-signaling proteins identified an enhanced GluA2-S880 phosphorylation in
prefrontal cortex in the mutant mice. In a screen of glutamate signaling genes in patients with autism, we found
gain-of-function mutations in GRIP1-PDZ4-6 that contribute to reduced social interactions in autism patients.
To study mechanisms of GluA2 trafficking in modulating social behaviors, we generated knock-in mice carrying
a human autism-associated mutation I586L. Grip1-I586L mice show increased binding with GluA2 in brain
lysates and exhibit a reduced sociability in the modified three-chamber sociability tests. We hypothesize that
Grip1-I586L alter GluA2 recycling and surface expression resulting in increased AMPA synaptic strength and
enhanced local connectivity in prefrontal cortex. We will study molecular mechanisms responsible for GluA2
trafficking defects in Grip1-KO and Grip1-I586L mice. We will investigate neural mechanisms of disturbance of
AMPA signaling in prefrontal cortex causing social behavioral deficits in autism using electrophysiology and
optogenetic methods. The results shall provide valuable insights into neural mechanisms of AMPA signaling
defects in social behavioral deficits in autism.

## Key facts

- **NIH application ID:** 10196966
- **Project number:** 5R01MH112808-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Richard L Huganir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $408,750
- **Award type:** 5
- **Project period:** 2017-09-18 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196966

## Citation

> US National Institutes of Health, RePORTER application 10196966, AMPA receptor trafficking regulates social behaviors in autism (5R01MH112808-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10196966. Licensed CC0.

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