A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 12/2010; 5(12):e14200. DOI: 10.1371/journal.pone.0014200
Source: PubMed


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.
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 exhibited similar deficits to support spine formation and structure than DS astrocytes.
These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions.

Download full-text


Available from: Pinar Coskun,
  • Source
    • "In adult brain, TSP-1 promotes structural and functional recovery of synapses compromised by stroke (Liauw et al. 2008), by a mechanism involving up-regulation of a neuroprotective cytokine Tumor growth factor-b1 (Cekanaviciute et al. 2014). Recently, impaired TSP-1 delivery from astrocytes to neurons has been implicated in the synaptic pathology associated with Down's syndrome (Garcia et al. 2010). In a study reported in this issue, Michael Norenberg's group presents data indicating that shortage of astroglia-derived TSP-1 may contribute to synaptic dysfunction in HE (Jayakumar et al. 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Read the full article ‘Decreased astrocytic thrombospondin‐1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies’ on page 333
    Journal of Neurochemistry 08/2014; 131(3). DOI:10.1111/jnc.12823 · 4.28 Impact Factor
  • Source
    • "herson et al . 2005 ; Eroglu et al . , 2009 ) , as well as accelerates synaptogenesis ( Xu et al . , 2010 ) . Astrocyte - derived TSP - 1 was also shown to mediate the development of pre - synaptic plasticity in vitro ( Crawford et al . 2012 ) . Conversely , defective astrocytic TSP - 1 release is known to be associated with neuronal dysfunction ( Garcia et al . 2010 ) . Yu et al . ( 2008 ) demonstrated that retinal ganglion cell survival and neurite outgrowth were improved when co - cultured with bone marrow stromal cells ( which are known to release TSP - 1 ) , a process mediated by the up - regulation of synaptophysin . On the other hand , decreasing TSP - 1 expression by siRNA silencing led to a"
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media (CM) from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95 and synaptotagmin levels. CM from TSP-1 overexpressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; 131(3). DOI:10.1111/jnc.12810 · 4.28 Impact Factor
  • Source
    • "In the CNS, TSPs 1 and 2 are expressed in cultured and developing astrocytes, with expression peaking during the first postnatal week in mice [102] [103]. In addition, high levels of TSP1 can be found in cultured human astrocytes [104] [105]. Astrocytesecreted TSP1/2 has been shown to be important for the formation of excitatory synapses in vitro and in vivo ([102] [106], recently reviewed extensively in [11] [101]). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Matricellular proteins are secreted, nonstructural proteins that regulate the extracellular matrix (ECM) and interactions between cells through modulation of growth factor signaling, cell adhesion, migration, and proliferation. Despite being well described in the context of nonneuronal tissues, recent studies have revealed that these molecules may also play instrumental roles in central nervous system (CNS) development and diseases. In this minireview, we discuss the matricellular protein families SPARC (secreted protein acidic and rich in cysteine), Hevin/SC1 (SPARC-like 1), TN-C (Tenascin C), TSP (Thrombospondin), and CCN (CYR61/CTGF/NOV), which are secreted by astrocytes during development. These proteins exhibit a reduced expression in adult CNS but are upregulated in reactive astrocytes following injury or disease, where they are well placed to modulate the repair processes such as tissue remodeling, axon regeneration, glial scar formation, angiogenesis, and rewiring of neural circuitry. Conversely, their reexpression in reactive astrocytes may also lead to detrimental effects and promote the progression of neurodegenerative diseases.
    Neural Plasticity 01/2014; 2014(8):321209. DOI:10.1155/2014/321209 · 3.58 Impact Factor
Show more