Molecular mechanisms of astrocyte-induced synaptogenesis

Abstract

Astrocytes are morphologically complex cells that perform a wide variety of critical functions in the brain. As a structurally and functionally integrated component of the synapse, astrocytes secrete proteins, lipids, and small molecules that bind neuronal receptors to promote synaptogenesis and regulate synaptic connectivity. Additionally, astrocytes are key players in circuit formation, instructing the formation of synapses between distinct classes of neurons. This review highlights recent publications on the topic of astrocyte-mediated synaptogenesis, with a focus on the molecular mechanisms through which astrocytes orchestrate the formation of synaptic circuits.

Figure 1

Astrocyte-secreted factors induce excitatory synapse formation. (a) Astrocytes secrete thrombospondins (TSP) which bind to neuronal α2δ-1 to induce the formation of silent, structural synapses. The anti-epileptic drug Gabapentin (GBP) binds to α2δ-1, preventing TSP-induced synaptogenesis. (b) Astrocyte-secreted Hevin/SPARCL1 promotes synapse formation through its interactions with presynaptic NRX1α and postsynaptic NL1B, two proteins that do not normally interact. Astrocyte-secreted SPARC antagonizes Hevin-induced synapse formation through an unknown mechanism. (c) Astrocyte-secreted TGF-β1 promotes the formation of excitatory synapses through a mechanisms that requires NMDA receptor activity, along with the NMDA receptor agonist D-serine.

Figure 2

Heterogeneity amongst reactive astrocytes. Following insult or injury, astrocytes enter a reactive state, characterized by changes in astrocyte morphology and gene expression. Depending on the stimulus, astrocytes can become neurotoxic A1 type reactive astrocytes, or neuroprotective A2 type reactive astrocytes. Neuroinflammatory stimuli, such as LPS, yield A1 reactive astrocytes, by activating microglia to secrete the inflammatory cytokines Il-1α, TNF, and C1q. A1 reactive astrocytes promote neurodegeneration and neurotoxicity, and are not synaptogenic. Interestingly, application of TGFβ and FGF can revert type A1 reactive astrocytes to a non-reactive state in vitro. Ischemia induces the formation of A2 reactive astrocytes, through an unknown mechanism. These astrocytes have a different gene signature from A1 reactive astrocytes, and secrete neurotrophic factors to promote neuroprotection and neural repair.