Contribution of astrocytic calcium signaling to auditory hypersensitivity in a mouse model of fragile X syndrome

Hypersensitivity to sensory stimuli is a common co-morbidity of Fragile X syndrome (FXS), the leading monogenic form of intellectual disability and autism spectrum disorder (ASD). Neuronal impairments associated with auditory and tactile hypersensitivity have been reported in the Fmr1 knockout mouse model of FXS. However, the contribution of astrocytes, in which Fmr1 is also expressed, to sensory hypersensitivity has not been defined. Using mice with astrocyte-specific deletion of Fmr1 (cKO) and mice with astrocyte-specific expression of Fmr1 (cON), we demonstrated that loss of astrocytic FMRP is sufficient but not necessary to confer susceptibility to audiogenic seizures (AGS), an indication of auditory hypersensitivity. Moreover, in vivo multiphoton imaging revealed increased astrocytic calcium signaling in Fmr1 KO mice. To test if enhanced astrocyte calcium signaling contributes to increased AGS, we crossed Fmr1 deletion mice to IP3R2 mutant mice. Reduced expression of IP3R2 rescued the AGS phenotype in the Fmr1 astrocyte cKO but not in the global Fmr1 KO mouse. Our results reveal that astrocytes contribute to AGS in mouse models of FXS through enhanced calcium signaling. • Astrocyte-specific deletion of FMRP is sufficient to cause auditory hypersensitivity in mice. • Astrocytes have enhanced calcium signaling in Fmr1 KO mice. • Reducing astrocyte calcium signaling corrects auditory hypersensitivity in mice with astrocyte-specific deletion of FMRP.