a role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in downs syndrome血小板反应蛋白- 1的作用赤字astrocyte-mediated脊椎和突触在唐氏综合征病理.pdfVIP

A Role for Thrombospondin-1 Deficits in Astrocyte- Mediated Spine and Synaptic Pathology in Down’s Syndrome Octavio Garcia, Maria Torres, Pablo Helguera, Pinar Coskun, Jorge Busciglio* Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders (iMIND), Center for the Neurobiology of Learning and Memory (CNLM), University of California Irvine, Irvine, California, United States of America Abstract Background: Down’s syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology. Methodology/Principal Findings: Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice