Abstract
The proper formation and maintenance of functional synapses in the central nervous system (CNS) requires communication between neurons and astrocytes and the ability of astrocytes to release neuromodulatory molecules. Previously, we described a novel role for the astrocyte-secreted matricellular protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) in regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and plasticity at developing synapses. SPARC is highly expressed by astrocytes and microglia during CNS development but its level is reduced in adulthood. Interestingly, SPARC has been shown to be upregulated in CNS injury and disease. However, the role of SPARC upregulation in these contexts is not fully understood. In this study, we investigated the effect of chronic SPARC administration on glutamate receptors on mature hippocampal neuron cultures and following CNS injury. We found that SPARC treatment increased the number of GluA1-containing AMPARs at synapses and enhanced synaptic function. Furthermore, we determined that the increase in synaptic strength induced by SPARC could be inhibited by Philanthotoxin-433, a blocker of homomeric GluA1-containing AMPARs. We then investigated the effect of SPARC treatment on neuronal health in an injury context where SPARC expression is upregulated. We found that SPARC levels are increased in astrocytes and microglia following middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Remarkably, chronic pre-treatment with SPARC prevented OGD-induced loss of synaptic GluA1. Furthermore, SPARC treatment reduced neuronal death through Philanthotoxin-433 sensitive GluA1 receptors. Taken together, this study suggests a novel role for SPARC and GluA1 in promoting neuronal health and recovery following CNS damage.
Highlights
Astrocytes communicate with neurons through secretion of active molecules to control synapse development, neuronal activity and plasticity (Clarke and Barres, 2013; Baldwin and Eroglu, 2017)
In our previous study we examined the role of SPARC during development and found that SPARC regulates the levels of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) during synapse maturation, which in turns modulates synaptic strength and plasticity (Jones et al, 2011)
Given our previous work showing that SPARC can regulate the strength of synapses during development, we decided to investigate the effect of increasing SPARC on surface AMPARs in hippocampal neuron cultures grown with a feeder layer of astrocytes
Summary
Astrocytes communicate with neurons through secretion of active molecules to control synapse development, neuronal activity and plasticity (Clarke and Barres, 2013; Baldwin and Eroglu, 2017). Many of the matricellular proteins in the CNS, such as SPARC, Hevin/SC1 (SPARC-like 1), Thrombospondins, Glypicans, CYR61/Connective Tissue Growth Factor/Nov family of proteins (CCN) and Tenascin C, are secreted from glial cells (Eroglu, 2009; Jones and Bouvier, 2014). These molecules are structurally unrelated, they share the general characteristic that they are highly expressed during development become downregulated to a low level in the mature CNS. Upon injury or disease, their expression has been shown to be upregulated, where they are well-positioned to contribute to repair processes such as tissue remodeling, proliferation, angiogenesis, and rewiring of neural circuitry (Jones and Bouvier, 2014)
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