Anding, A. | bioRxiv Science

bioRxiv2025

Activity of Human-Specific Interlaminar Astrocytes in a Chimeric Mouse Model of Fragile X Syndrome

Astrocytes, a subtype of glial cells, have multiple roles in regulating neuronal development and homeostasis. In addition to the typical mammalian astrocytes, in the primate cortex interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. Previously, we described a human stem cell based chimeric mouse model where interlaminar astrocytes develop. Here, we utilized this model to study the calcium signaling properties of interlaminar astrocytes. To determine how interlaminar astrocytes could contribute to neurodevelopmental disorders, we generated a chimeric mouse model for Fragile X syndrome. We report that FXS interlaminar astrocytes exhibit hyperexcitable calcium signaling and are associated with dendritic spines with increased turnover rate.

neuroscience↗

bioRxiv2025

Astrocytic contribution to sensory hypersensitivity in a mouse model of fragile X syndrome

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 messenger ribonucleoprotein gene 1 (FMR1), which result in complete or partial loss of expression of its protein product, fragile X messenger ribonucleoprotein (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 stimuli, but how astrocytes contribute to hypersensitivity in the context of FXS remains unknown. Using mice with astrocyte-specific reduction of Fmr1 (Fmr1 conditional KO (cKO)) and mice with astrocyte-specific expression of Fmr1 (Fmr1 cON), we demonstrated that reduction of astrocytic FMRP is sufficient but not necessary to confer susceptibility to audiogenic seizures, an indication of auditory hypersensitivity. In addition, reduction of astrocytic FMRP impacts neuronal activity, resulting in spontaneous seizures. In contrast, we assessed tactile hypersensitivity using a whisker stimulation paradigm but did not detect significant differences in Fmr1 cKO mice. Our results reveal that astrocytes lacking FMRP contribute to auditory hypersensitivity and spontaneous seizures.

neuroscience↗