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Abstract
FMR1 CGG expansion repeats in the premutation range have not been linked to astrocyte pathophysiology. Premutation cortical astrocytes display decreased Glu transporter expression/activity and enhanced asynchronous Ca(2+) oscillations. Glu transport and Ca(2+) signaling defects in premutation astrocytes could contribute to FXTAS neuropathology. Premutation astrocytes may have an etiological role in FXTAS neuropathology. Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene can cause fragile X-associated tremor/ataxia syndrome. Defects in early neuronal migration and morphology, electrophysiological activity, and mitochondria trafficking have been described in a premutation mouse model, but whether preCGG mutations also affect astrocyte function remains unknown. PreCGG cortical astrocytes (∼170 CGG repeats) displayed 3-fold higher Fmr1 mRNA and 30% lower FMR1 protein (FMRP) when compared with WT. PreCGG astrocytes showed modest reductions in expression of glutamate (Glu) transporters GLT-1 and GLAST and attenuated Glu uptake (p < 0.01). Consistent with astrocyte cultures in vitro, aged preCGG mice cerebral cortex also displayed reduced GLAST and GLT-1 expression. Approximately 65% of the WT and preCGG cortical astrocytes displayed spontaneous asynchronous Ca(2+) oscillations. PreCGG astrocytes exhibited nearly 50% higher frequency of asynchronous Ca(2+) oscillations (p < 0.01) than WT, a difference mimicked by chronic exposure of WT astrocytes to l-trans-pyrrolidine-2,4-dicarboxylic acid (l-trans-PDC) or by partial suppression of GLAST using siRNA interference. Acute challenge with Glu augmented the frequency of Ca(2+) oscillations in both genotypes. Additionally, 10 μm Glu elicited a sustained intracellular Ca(2+) rise in a higher portion of preCGG astrocytes when compared with WT. Pharmacological studies showed that mGluR5, but not NMDA receptor, contributed to Glu hypersensitivity in preCGG astrocytes. These functional defects in preCGG astrocytes, especially in Glu signaling, may contribute to fragile X-associated tremor/ataxia syndrome neuropathology.
Highlights
fragile X mental retardation 1 (FMR1) CGG expansion repeats in the premutation range have not been linked to astrocyte pathophysiology
PreCGG Cortical Astrocytes Display Elevated Fmr1 mRNA and Modestly Reduced FMR1 protein (FMRP)—Given the ubiquitin-positive nuclear inclusions observed in astrocytes in the brains of premutation CGG expansion (preCGG) KI mice [15, 32], we first examined the Fmr1 mRNA levels in both preCGG and wild type (WT) cortical astrocyte cultures
We demonstrate that cortical astrocytes isolated from heterozygous KI mice with premutation CGG expansions (ϳ170 repeats) display ϳ3-fold higher Fmr1 mRNA levels, yet 30% reduced FMRP expression when compared with paired astrocyte cultures from WT mice
Summary
FMR1 CGG expansion repeats in the premutation range have not been linked to astrocyte pathophysiology. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult onset neurodegenerative disorder that occurs in individuals with a trinucleotide expansion (55–200 CGG repeats, premutation) within the fragile-X mental retardation 1 (FMR1) gene. The ubiquitin-positive intranuclear inclusions are present notably in a higher percentage in human cortical gray matter astrocytes (17%) than in neurons (4%) [18, 19, 33] These data indicate that the FMR1 CGG expansion repeats in the premutation range might trigger functional abnormalities in astrocytes that promote neuropathology. When compared with the wild type (WT) controls, preCGG cortical astrocytes exhibit more frequent spontaneous Ca2ϩ oscillations and reduced expression of Glu transporters GLAST and GLT-1, consistent with attenuated Glu uptake. Pharmacological suppression of Glu transporters activity or decrease in the GLAST expression using GLAST siRNA enhances spontaneous asynchronous Ca2ϩ oscillations in WT astrocytes similar to those observed in preCGG astrocytes, suggesting that reduced Glu uptake may contribute to altered Ca2ϩ dynamics observed in preCGG astrocytes
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