Schedule of Events | Symposia

Astrocytic Cholesterol Dysregulation in Fragile X Syndrome

Poster Session D - Monday, March 31, 2025, 8:00 – 10:00 am EDT, Back Bay Ballroom/Republic Ballroom

Joy Nguyen¹ (jnguy851@medsch.ucr.edu), Luis Hernandez², Victoria Wagner³, Iryna Ethell⁴; ¹UCR SOM

Fragile X Syndrome (FXS) is the most common inherited intellectual disability, affecting 1 in 4,000 males and 1 in 8,000 females worldwide. It is caused by a mutation in the FMR1 gene, resulting in the loss of FMRP. Lovastatin, a cholesterol-lowering drug, has been shown to reduce the frequency and severity of audiogenic seizures in FXS patients. Deficits in synapse development may underlie the hyperexcitable circuits and behavioral symptoms observed in FXS. Cholesterol, a critical synaptic component, is supplied to neurons by astrocytes. Dysregulated cholesterol homeostasis in astrocytes could explain lovastatin's beneficial effects (Talvio K. et al. Commun Biol 6, 789 (2023)). This study examines the impact of FMRP loss on cholesterol regulation in astrocytes. We analyzed gene expression of cholesterol-regulating proteins in three brain regions critical to cortical hypersensitivity and behavioral deficits in FXS (frontal cortex, temporal cortex, and hippocampus) from 5 wildtype and 4 FMRP astrocyte-specific conditional knockout mice. A significant reduction in the ABCA1 expression was observed in the hippocampus of knockout mice. ABCA1 is a transmembrane efflux protein responsible for cholesterol transport out of cells. These findings suggest that FMRP loss leads to cholesterol accumulation in hippocampal astrocytes, impairing their function. As demonstrated in Li Xiaohui, et al., neurons may then need to synthesize their own cholesterol, an energetically costly process that diverts acetyl-CoA, potentially disrupting histone acetylation and epigenetic modifications critical for learning and memory. Our study provides insight into a potential mechanism underlying the therapeutic benefits of lovastatin in FXS patients.

Topic Area: EMOTION & SOCIAL: Development & aging