Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC

Abstract

Astrocytes regulate synaptic connectivity in the CNS through secreted signals. Here we identified two astrocyte-secreted proteins, hevin and SPARC, as regulators of excitatory synaptogenesis in vitro and in vivo. Hevin induces the formation of synapses between cultured rat retinal ganglion cells. SPARC is not synaptogenic, but specifically antagonizes synaptogenic function of hevin. Hevin and SPARC are expressed by astrocytes in the superior colliculus, the synaptic target of retinal ganglion cells, concurrent with the excitatory synaptogenesis. Hevin-null mice had fewer excitatory synapses; conversely, SPARC-null mice had increased synaptic connections in the superior colliculus. Furthermore, we found that hevin is required for the structural maturation of the retinocollicular synapses. These results identify hevin as a positive and SPARC as a negative regulator of synapse formation and signify that, through regulation of relative levels of hevin and SPARC, astrocytes might control the formation, maturation, and plasticity of synapses in vivo.F ormation of the correct type and number of synaptic connections is crucial for the proper development and function of our nervous systems. In the past decade, astrocytes have emerged as important regulators of synaptic connectivity (1, 2).By using a purified retinal ganglion cell (RGC) culture system (3), we previously showed that astrocyte-secreted factors, including a family of ECM proteins, thrombospondins (TSPs), significantly increase the number of synapses formed between RGCs (4-6). These in vitro findings paved the way for recognition of astrocytes, and the TSPs they secrete, as important regulators of synapse formation and injury-mediated synaptic remodeling in vivo (4,5,7).TSPs belong to a subclass of secreted proteins called matricellular proteins. Matricellular proteins function by modulation of cell-cell and cell-matrix interactions, and thereby regulate the adhesion state of cells (8). Astrocytes express a number of matricellular proteins in addition to TSPs, and their expression is developmentally regulated and overlaps with early postnatal periods of synaptic development in the CNS (9, 10).In the present study we investigated whether other astrocytesecreted matricellular proteins could modulate synapse formation. Gene expression profiling of astrocytes suggested the matricellular proteins hevin [also known as secreted protein acidic and rich in cysteine (SPARC)-like 1] and SPARC as possible candidates. Hevin and SPARC are members of the SPARC family (11). Hevin was first identified as a synaptic glycoprotein and was initially termed synaptic cleft-1, or SC1 (12). It is localized to excitatory CNS synapses (13). Astrocytes in the developing brain express high levels of hevin and SPARC mRNA, with hevin mRNA being one of the highest-level mRNAs expressed by astrocytes (10). Unlike TSP1 and TSP2, the expression of which is decreased during maturation, hevin and SPARC mRNA levels remain high in the adult (9, 14-16).Here we investigated whether hevin and SPARC p...

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“…Interestingly, the protein SPARC is also released by astrocytes and functions to inhibit the synaptogenic action of hevin (Kucukdereli et al, 2011). The positive and negative actions of these molecules on synapse formation demonstrate that astrocytes can carefully tune the formation of synaptic elements in a bidirectional manner.…”

“…In addition to TSPs, the secreted matricellular protein hevin (also known as secreted protein acidic and rich in cysteine (SPARC)-like 1, or SPARCL1) is important for RGC synapse formation in vitro and for establishing synaptic connectivity to the superior colliculus in vivo (Kucukdereli et al, 2011). Interestingly, the protein SPARC is also released by astrocytes and functions to inhibit the synaptogenic action of hevin (Kucukdereli et al, 2011).…”