Fig 1. Schematic illustration of the synapse model.

Pre- and postsynaptic neurons and a fine astrocyte process are presented with key model components. (1) Presynaptic membrane potential depends on currents via Ca_NHVA, Na⁺, and K⁺ channels as well as via NMDARs. Presynaptic action potential and Ca_NHVA- and NMDAR-mediated Ca²⁺ concentrations together with the influence of CaN affect the vesicular release. (2) The released glutamate in the synaptic cleft activates postsynaptic mGluRs, NMDARs, and AMPARs in addition to presynaptic NMDARs. (3) Postsynaptic membrane potential in the soma depends on currents via Na⁺, Na_P, and K_DR channels, whereas postsynaptic membrane potential in the dendrite depends on currents via Ca_LHVA, Ca_LLVA, Na⁺, and K_A channels as well as via NMDARs and AMPARs. The activation of postsynaptic mGluRs and NMDARs, together with the Ca_LHVA- and Ca_LLVA-mediated Ca²⁺ influx, triggers a G-protein signaling cascade where GαGTP dissociates from mGluR-bound Gβγ and activates PLC and production of DAG and IP₃. Increases in Ca²⁺ and IP₃ concentrations activate Ca²⁺ release via IP₃Rs from the ER to the cytosol. On the other hand, PMCA and SERCA pumps transfer Ca²⁺ away from the cytosol and leak fluxes transfer Ca²⁺ back to the cytosol. The production of DAG leads to a production of endocannabinoid 2-AG. (4) Endocannabinoid 2-AG released from the postsynaptic neuron binds to the astrocytic CB₁Rs and triggers Ca²⁺ signaling in the astrocyte. We modeled this step by directly modifying astrocytic IP₃ concentration based on the postsynaptic 2-AG concentration. (5) Astrocytic IP₃ and Ca²⁺ activate similar ER-related events as in the postsynaptic neuron. Astrocytic Ca²⁺ increase then induces glutamate exocytosis to the extrasynaptic space. (6) Glutamate in the extrasynaptic space and the spillover of glutamate from the synaptic cleft activate presynaptic NMDARs. (7) Presynaptic NMDAR-mediated Ca²⁺ concentration activates CaN, and CaN has an effect on vesicular release together with presynaptic action potential and Ca_NHVA-mediated Ca²⁺ concentration.