Abstract
Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Defects in astrocyte signaling are implicated in neurodevelopmental disorders characterized by abnormal neural circuitry such as Fragile X syndrome (FXS). In animal models of FXS, the loss in expression of the Fragile X mental retardation 1 protein (FMRP) from astrocytes is associated with delayed dendrite maturation and improper synapse formation; however, the effect of astrocyte-derived factors on the development of neurons is not known. Thrombospondin-1 (TSP-1) is an important astrocyte-secreted protein that is involved in the regulation of spine development and synaptogenesis. In this study, we found that cultured astrocytes isolated from an Fmr1 knockout (Fmr1 KO) mouse model of FXS displayed a significant decrease in TSP-1 protein expression compared to the wildtype (WT) astrocytes. Correspondingly, Fmr1 KO hippocampal neurons exhibited morphological deficits in dendritic spines and alterations in excitatory synapse formation following long-term culture. All spine and synaptic abnormalities were prevented in the presence of either astrocyte-conditioned media or a feeder layer derived from FMRP-expressing astrocytes, or following the application of exogenous TSP-1. Importantly, this work demonstrates the integral role of astrocyte-secreted signals in the establishment of neuronal communication and identifies soluble TSP-1 as a potential therapeutic target for Fragile X syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0256-9) contains supplementary material, which is available to authorized users.
Highlights
Fragile X syndrome (FXS) is the most common form of intellectual disability and is a leading cause of autism spectrum disorders [1], affecting about 1/4000 males and 1/8000 females
fragile x mental retardation gene 1 (Fmr1) knockout neurons display dendritic spine and synaptic abnormalities relative to their wildtype counterparts Previous reports have established the critical role of astrocytes in FXS [9, 10]; the role of astrocytes in regulating dendritic spine formation has not been elucidated
Consistent with previous studies showing that astrocyte-conditioned medium (ACM) induces synapse formation [17], we found that the addition of WT ACM to Fmr1 knockout (Fmr1 KO) neurons significantly increased the number of synaptophysin/PSD95 co-localized puncta per 50 μm length of dendrite (Fig. 4e, p < 0.05)
Summary
Fragile X syndrome (FXS) is the most common form of intellectual disability and is a leading cause of autism spectrum disorders [1], affecting about 1/4000 males and 1/8000 females. The causative mutation for the majority of cases is a trinucleotide CGG expansion in the promoter region of the fragile X mental retardation 1 gene (FMR1), which induces transcriptional gene silencing and the loss of the fragile X mental retardation 1 protein (FMRP). The majority of research into the function of FMRP, and the consequences of its absence, has largely been focused on neurons. The expression of FMRP is typically highest in astrocytes within the first week of birth and subsequently declines to low or undetectable levels [8]. Based on these findings, work in our laboratory investigated the role of
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