Figure 8

Schematic diagram of proposed physiological roles for Ca ²⁺ -dependent astrocytic glutamate release via Best1 channel in synaptic plasticity. We propose a model for the modulation of synaptic function via the action of astrocytic Best1-mediated glutamate on postsynaptic NMDARs. A, Astrocytic GPCR is activated by neurotransmitter or neuronal factors. B, Downstream signaling pathways induce release of Ca²⁺ from internal stores, resulting in an increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) at microdomains that wrap around synaptic terminals. C, Increased microdomain Ca²⁺ activates the Ca²⁺-dependent glutamate-permeable anion channel (Best1), leading to glutamate efflux from astrocytes. D, Best1-mediated glutamate binds to synaptically localized NMDAR (GluN2A). E, Glutamate released from presynaptic neuron activates AMPAR, which causes postsynaptic depolarization. F, When postsynaptic depolarization resulting from synaptic activity is accompanied by the binding of astrocytic glutamate to synaptic NMDARs, Ca²⁺ influx to postsynaptic sites is increased, resulting in the enhanced Ca²⁺-dependent signaling required for increasing synaptic strength.