Ca2+ and Glu Signaling in FMR1 preCGG Astrocytes [Neurobiology]

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 Ca2+ oscillations. PreCGG astrocytes exhibited nearly 50% higher frequency of asynchronous Ca2+ 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 Ca2+ oscillations in both genotypes. Additionally, 10 μm Glu elicited a sustained intracellular Ca2+ rise in a higher portion of preCGG astrocytes when compared with WT. Pharmacological studies showed that mGluR5, but not...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research