Fig. 4

a Proposed model of the states in ion channel mediated synaptic scaling. In the active synapse calcium influx through the NMDA receptor activates CaMKII that utilizes ATP to phosphorylate DLGAP that causes dissociation from DLG4 and SHANK and prones them for ubiquitination (Ub). Subsequently, DLGAP, DLG4 and SHANK are degraded, which results in endocytosis of the AMPA and NMDA receptors. During synaptic inactivation the scaffold proteins DLGAP, DLG4 and SHANK accumulate together with the AMPA and NMDA receptors that are incorporated in the membrane. b Proposed model of mGluR mediated synaptic scaling displayed as an equilibrium between the active and the inactive synapse. The synaptic scaling is initiated by activation of mGluR1/5 by glutamate followed by PLC-mediated membrane release of DAG. The release of DAG leads to activation of PKC and release of intracellular Ca²⁺. The increase in calcium ions activates CaMKII that phosphorylates DLGAP and Homer. After phosphorylation DLGAP dissociates from DLG4 and SHANK, and Homer dissociates from mGluR1/5 and SHANK. DLGAP, DLG4, Homer and SHANK are then ubiquitinated (Ub) and degraded. With no intracellular bound scaffold proteins, NMDA receptors and AMPA receptors are internalised and removed from the synapse. In the inactive synapse after activation the scaffold proteins DLGAP, DLG4, Homer and SHANK accumulate together with AMPA receptors and NMDA receptors that are incorporated into the membrane. c Working model of endocannabinoid-mediated synaptic depression that is initiated by glutamate stimulation of mGluR1/5 that leads to PLC-mediated release of DAG. Then, DAG is converted to the endocannabinoid 2-AG that is transported to the synaptic cleft where it binds to the endocannabinoid receptor CB1R. After activation of CB1R, glutamate release from the presynapse to the synaptic cleft is halted, which leads to the depression. Presence of DLGAP in the PSD inhibits this endocannabinoid synaptic depression most likely via a DLGAP-SHANK-Homer- mGluR1/5