Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Anna Dunaevsky

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism spectrum disorder (ASD). FXS is caused by mutations in the fragile X mental retardation gene (FMR1), which result in complete or substantial loss of expression of its protein product fragile X mental retardation protein (FMRP). Neuronal impairments in the absence of FMRP have been extensively characterized. However, much less is known about the impact that loss of FMRP has on the physiology and function of astrocytes and the implications for behavior. A common behavior exhibited by both FXS and ASD patients is hypersensitivity to sensory (tactile, auditory, or visual) stimuli, but how astrocytes contribute to hypersensitivity in the context of FXS remains unknown. Using a whisker stimulation assay to assess tactile hypersensitivity, we found that mice with astrocyte-specific deletion of Fmr1 (Fmr1 cKO) show enhanced avoidance of the stimuli, indicative of tactile defensiveness, a form of sensory hypersensitivity. Using Fmr1 cKO mice and mice with astrocytic-specific expression of Fmr1 (Fmr1 cON), we demonstrated that loss of astrocytic FMRP is sufficient and necessary to confer susceptibility to audiogenic seizures, an indication of auditory hypersensitivity. Fmr1 cKO mice also exhibit electrographic seizures and altered neural oscillations. To determine how loss of FMRP impacts astrocyte activity, we performed two-photon imaging to characterize spontaneous and ATP-induced astrocytic Ca2+ events in brain slices from Fmr1 KO mice and Fmr1 cKO mice. We found that astrocytes from Fmr1 KO mice exhibit enhanced Ca2+ signaling, but this was not observed in Fmr1 cKO, indicating this is not a cell autonomous effect. Audiogenic seizures are prevented in Fmr1 cKO mice with reduced expression of the inositol 1,4,5-trisphosphate type 2 receptor, a key mediator of somatic Ca2+ signaling in astrocytes, indicating aberrant astrocytic Ca2+ signaling may contribute to sensory hypersensitivity. We conclude that loss of astrocytic FMRP contributes to tactile and auditory hypersensitivity in mouse models of FXS and that a lack of FMRP causes aberrant astrocytic Ca2+ signaling.

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