Astroglia-Mediated Pathogenic Mechanisms in Fragile X Syndrome (FXS)

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Abstract Fragile X syndrome (FXS) is one of the most common inherited intellectual disabilities (ID) that is caused by transcriptional silencing of the Fmr1 gene and loss of its encoded fragile X messenger ribonucleoprotein (FMRP). FXS manifests with cognitive impairment, hyperactivity/seizure, sensory hypersensitivity, and several autistic features such as repetitive behaviors and social withdraw. FMRP has been shown to be primarily a RNA- binding protein that regulates translation of many mRNAs. In the mammalian CNS, astroglial cells play active and diverse roles in modulating synaptogenesis and synaptic functions, especially during postnatal development. How the loss of FMRP affects astroglial development and functions, especially underlying molecular mechanisms, just begin to be understood. MicroRNAs (miRs) are a class of noncoding RNAs with a mature length of 20-25 nucleotides that primarily bind to the 3’UTR of target mRNAs to significantly modulate gene expression by either inhibiting mRNA translation or inducing mRNA degradation. Biochemical and genetic evidence in neurons have implicated important roles of miR pathways in FMRP-mediated translational regulation. Additionally, miRs play key roles in the specification of neural progenitor cells and oligodendrocyte and microglia developmental maturation. Surprisingly, how miRs are involved in astroglial development especially postnatal molecular and morphological maturation is essentially unknown. This represents a significant obstacle to better understand astroglia-mediated pathogenic pathways in FXS. Based on our preliminary results and progress we made during previous funding period in understanding the role of astroglia in FXS pathogenesis, in this renewal, we propose the following aims: Aim 1: Determine the roles of miR-128-3p in regulating postnatal astroglial development; Aim 2: Determine the pathogenic roles of increased astroglial miR-128-3p in FXS. We have generated astroglial miR-128 conditional knock-out (Astro- miR-128 CKO) and astroglial miR-128/Fmr1 double conditional knock-out (Astro-miR-128/Fmr1 DCKO) mice and have generated a large amount of preliminary data to support our rationales and to demonstrate feasibility for proposed aims. We will employ mouse genetics, primary astroglial cultures, electrophysiology, virus injections, confocal and immunoEM imaging, and behavioral approaches to complete these aims. Outcomes from this project will begin to define specific miRs that regulate postnatal astroglial molecular and morphological maturation. In addition, the analysis of FXS-relevant synaptic and behavioral phenotypes on Astro-miR-128/Fmr1 DCKO mice will potentially provide a new astroglial target to modulate FXS disease development, thus will significantly advance our understanding about astroglial mechanisms in FXS pathogenesis.