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

Abstract

BackgroundDown'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 FindingsUsing 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.Conclusions/SignificanceThese 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.

Emerging roles of astrocytes in neural circuit development

“…Furthermore, TSP1 levels were markedly reduced in astrocytes from patients with Down’s syndrome. The restoration of TSP1 levels rescued the spine and synaptic defects found in hippocampal neurons cultured in the presence of Down’s syndrome astrocytes 107 . These results indicate that astrocyte-secreted molecules contribute to the synaptic defects in Down’s syndrome and raise the question of whether TSP1 could be used to treat these synaptic defects.…”

“…The cognitive deficits in patients with Down’s syndrome have been associated with structural changes in the architecture and alterations in the number of dendritic spines 106 . Hippocampal neurons grown in the presence of astrocytes from patients with Down’s syndrome have abnormal spine development and reduced synaptic density and activity 107 . This study identified TSP1 as the key astrocyte-secreted factor that modulates spine number and density.…”

Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain

“…Astrocytes secrete a number of molecules that are not defined as gliotransmitters but that nevertheless directly modulate synaptic structures and thereby synaptic function (23) on a slower time scale. We focused on one class of these, the TSPs, because (a) they bind to synaptic α 2 δ-1 receptors to induce excitatory synaptogenesis in vitro and in vivo; (b) gabapentin, which inhibits this synaptogenic action by antagonizing TSP binding to α 2 δ-1, is effective against neuropathic pain (32); (c) dendritic spine malformations and reduced synaptic density in Down syndrome brain are directly linked to deficits in astrocytic TSP-1 protein expressions (56); and (d) astrocytes near the injured neuronal cell bodies release TSPs to cause functional and structural synaptic plasticity in vitro and in vivo (50,55). We found that TSP-1 release from S1 astrocytes is markedly increased 1 9 9 3 jci.org…”

Cell Biology of Astrocyte-Synapse Interactions

“…In Down's syndrome, a related neurodevelopmental disorder caused by trisomy of chromosome 21, astrocytes also do not support neuronal development or synapse formation, with WT neurons showing immature spines when cultured with Down's syndrome astrocytes. Interestingly, Down's syndrome astrocytes show decreased expression of multiple synaptogenic proteins including TSP1 and Gpc6, and like with Fragile X syndrome, the addition of TSP1 to Down's syndrome astrocytes is sufficient to rescue some of the synaptogenic deficits (Chen et al, 2014; Garcia et al, 2010). Finally in Costello syndrome, caused by mutations in HRAS, an opposite alteration in astrocyte function is observed.…”