# Molecular and cellular basis for autism spectrum disorders caused by exacerbated translation

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $536,596

## Abstract

Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with deficits in two core domains: social
interaction and communication, and repetitive behaviors or restrictive behaviors. It is diagnosed four times
more frequently in boys than in girls. Among a large number of risk loci for ASD, elevated protein synthesis has
been recognized as a converging pathological mechanism. ASD is associated with a high percentage of
patients with inactivating mutations in genes for several negative translation regulators, such as PTEN, TSC1,
TSC2 and FMR1. These mutations increase the availability of eukaryotic translation initiation factor 4E (eIF4E),
consequently elevating translation of a selective group of mRNAs. However, it remains unknown in which type
of brain cells and how elevated translation leads to dysfunction of neural circuits and subsequently ASD
behaviors. We have generated a knock-in mouse strain in which eIF4E is overexpressed from the Rosa26
locus in a Cre-dependent manner. We found that eIF4E overexpression in microglia, but not neurons or
astrocytes, led to ASD-like synaptic and behavioral aberrations only in male mice, including increased dendritic
spine density, excitation/inhibition imbalance, social interaction impairment, increased repetitive behavior, and
selective cognitive deficits. We further found that microglial eIF4E overexpression elevated translation in both
sexes but only increased microglial density and size in males. Given critical roles of microglia in synapse
development, we posit that elevated synthesis of some proteins alters microglial functions only in male mice,
which in turn impairs synapse development and thereby male-biased ASD. We will test this hypothesis in the
following three specific aims. Aim 1 is to investigate the molecular mechanism by which elevated protein
synthesis alters microglia; Aim 2 is to understand the mechanism underlying the sexual dimorphism of ASD-
like phenotypes in MG4E mice; Aim 3 is to determine how microglial alterations impact synapse development by
imaging in vivo dynamics of dendritic spines and microglia in control and MG4E mice. This research project will
not only provide insights into the pathological mechanism by which mutations in negative translation regulators
lead to ASD, but also show microglial dysfunction as a possible etiology of ASD. It may also uncover a
mechanism that underlies the strong male bias of ASD, which could guide strategies for innovative therapies of
the disorder.

## Key facts

- **NIH application ID:** 10697387
- **Project number:** 5R01MH125187-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** GAVIN R RUMBAUGH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $536,596
- **Award type:** 5
- **Project period:** 2022-04-03 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10697387

## Citation

> US National Institutes of Health, RePORTER application 10697387, Molecular and cellular basis for autism spectrum disorders caused by exacerbated translation (5R01MH125187-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10697387. Licensed CC0.

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