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
    • "Recently, it has been shown that astroglial dysfunction is also associated with intellectual disability in Down's syndrome (DS). DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules such as TSP1 and TSP2, leading to the abnormal development of dendritic spines and the reduced activity and density of synapses (Chen et al., 2014; Garcia et al., 2010). Interestingly, several of these abnormalities were prevented by the presence of normal astrocytes (Chen et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the last decade, there have been major advances in the understanding of the role of glial cells as key elements in the formation, maintenance and refinement of synapses. Recently, the discovery of natural compounds capable of modulating nervous system function has revealed new perspectives on the restoration of the injured brain. Among these compounds, flavonoids stand out as molecules easily obtainable in the diet that have remarkable effects on cognitive performance and behavior. Nevertheless, little is known about the cellular and molecular mechanisms underlying the actions of flavonoids in the nervous system. The present review presents recent advances in the effects of natural compounds, particularly flavonoids, in the nervous system. We shed light on astrocytes as targets of flavonoids and discuss how this interaction might contribute to the effects of flavonoids on neuronal survival, differentiation and function. Finally, we discuss how the effects of flavonoids on astrocytes might contribute to the development of alternative therapeutic approaches to the treatment of neural diseases.
    Full-text · Article · Feb 2016 · Neurochemistry International
  • Source
    • "Original theories regarding the disease focused almost exclusively on neurons, but recent evidence now indicates that glial cells (astrocytes, microglia and oligodendrocytes) are important contributors to disease pathology (reviewed inGuizzetti et al., 2014). Disruptions in astrocyte development and function may contribute to autism, fragile X, Down syndrome, Costello syndrome, neurofibromatosis-1, Noonan syndrome and Cardiofaciocutaneous syndrome (Garcia et al., 2010;Jacobs and Doering, 2010;Sloan and Barres, 2014). Astrocyte dysfunction is also hypothesized to partially underlie the neurodevelopmental origins of major depressive disorder (MDD) and schizophrenia as evidenced by glial anomalies in patients with these disorders (Sloan and Barres, 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol abuse during pregnancy may lead to fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and compromised cognitive and behavioral functions. Ethanol interferes with every step of central nervous system development; the cognitive and behavioral abnormalities associated with prenatal alcohol exposure are therefore due to a combination of effects exerted by ethanol throughout gestation. This chapter describes the physical and neurobehavioral consequences of in utero alcohol exposure and the brain structures affected in humans. Animal models used in FASD research are also described. Finally, this chapter provides an overview of the main mechanisms implicated in the developmental effects of ethanol as well as of experimental treatments under investigation for the amelioration of the consequences of FASD.
    Full-text · Article · Dec 2015
  • 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
    Full-text · Article · Aug 2014 · Journal of Neurochemistry
Show more