Thursday, November 21, 2024
11/21/2024
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.
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