Figure 2.

Astrocyte and microglia regulation of synaptic formation, function, and elimination, and potential implications for disease. A) Astrocytes (blue) and microglia (green) release soluble factors that regulate excitatory synapse formation and function. Aberrations in these processes may be relevant for epilepsy and schizophrenia. B) Glia refine synaptic circuits by engulfing synapses. MEGF10 and MERTK are astrocytic receptors required for synapse phagocytosis. MEGF10 and MERTK may detect synapses for elimination through bridging molecules such as Gas6 and Pros1 for Mertk that bind “eat me signals” on less active synapses. The identities of “synaptic eat me signals” for both receptors and bridging molecules for Megf10 are unknown. Microglia synapse pruning is dependent on the receptors CX3CR1 and CR3. The ligand of CX3CR1 is the neuronal CX3CL1 (fractalkine), which can either be membrane targeted or secreted. CR3 binds to C3, which may tag less active synapses and target them for elimination. Glial synapse elimination may be dysregulated in AD, ASD, schizophrenia, or other neuropsychiatric diseases. C) Astrocyes and microglia regulate synaptic transmission and plasticity. Astrocytes buffer K+ mostly through Na+/K+ ATPase and uptake glutamate through GLT1 and GLAST. Astrocytes also secrete D-serine and mediate synaptic plasticity. Microglia can impact synaptic plasticity through release of ROS, IL-1β, IL-6, and TNF. Microglia receptors required for proper synaptic function include CX3CR1 (with its ligand CX3CL1/fractalkine), as well as TREM2 and its downstream effector DAP12. These mechanisms may be important for ASD and schizophrenia.