Beneficial effects of sound exposure on auditory cortex development in a mouse model of Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the most common genetic cause of autism and intellectual disability. Fragile X mental retardation gene (Fmr1) knock-out (KO) mice display core deficits of FXS, including abnormally increased sound-evoked responses, and show a delayed development of parvalbumin (PV) cells. Here, we present the surprising result that sound exposure during early development reduces correlates of auditory hypersensitivity in Fmr1 KO mice. METHODS: Fmr1 KO and wild-type (WT) mice were raised in a sound-attenuated environment (AE) or sound-exposed (SE) to 14 kHz tones (5 Hz repetition rate) from P9 until P21. At P21-P23, event-related potentials (ERPs), dendritic spine density, PV expression and phosphorylation of tropomyosin receptor kinase B (TrkB) were analyzed in the auditory cortex of AE and SE mice. RESULTS: Enhanced N1 amplitude of ERPs, impaired PV cell development, and increased spine density in layers (L) 2/3 and L5/6 excitatory neurons were observed in AE Fmr1 KO compared to WT mice. In contrast, developmental sound exposure normalized ERP N1 amplitude, density of PV cells and dendritic spines in SE Fmr1 KO mice. Finally, TrkB phosphorylation was reduced in AE Fmr1 KO, but was enhanced in SE Fmr1 KO mice, suggesting that BDNF-TrkB signaling may be regulated by sound exposure to influence PV cell development. CONCLUSIONS: Our results demonstrate that sound exposure, but not attenuation, during early developmental window restores molecular, cellular and functional properties in the auditory cortex of Fmr1 KO mice, and suggest this approach as a potential treatment for sensory phenotypes in FXS.

An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.