Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model.
Mol Brain
; 9(1): 74, 2016 08 02.
Article
em En
| MEDLINE
| ID: mdl-27485117
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Coluna Vertebral
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Sinapses
/
Astrócitos
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Trombospondina 1
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Síndrome do Cromossomo X Frágil
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Brain
Assunto da revista:
BIOLOGIA MOLECULAR
/
CEREBRO
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Canadá