title: Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model.
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.
authors.affiliation: McMaster Integrative Neuroscience Discovery and Study Program (MINDS), McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4L8, Canada.|Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, HSC 1R15A, Hamilton, Ontario, L8N 3Z5, Canada.
authors.forename: Connie
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, HSC 1R15A, Hamilton, Ontario, L8N 3Z5, Canada.
authors.forename: Sally K M
authors.initials: SK
authors.lastname: Lau
authors.affiliation: McMaster Integrative Neuroscience Discovery and Study Program (MINDS), McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4L8, Canada. doering@mcmaster.ca.|Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, HSC 1R15A, Hamilton, Ontario, L8N 3Z5, Canada. doering@mcmaster.ca.
authors.forename: Laurie C
authors.initials: LC
authors.lastname: Doering
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D061252:Feeder Cells / Q000378:metabolism; D005260:Female; D005600:Fragile X Syndrome / Q000378:metabolism* / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D013131:Spine / Q000187:drug effects / Q000473:pathology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019700:Thrombospondin 1 / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D019700:Thrombospondin 1
keywords: Astrocytes; Autism; Dendritic spines; Fragile X syndrome; Secreted factor; Synapses; Thrombospondin-1