Fig. 7: In silico simulations confirm that AMPAR untrapping induced both a depression of synaptic currents and an increase of synaptic responsiveness. | Nature Communications

Fig. 7: In silico simulations confirm that AMPAR untrapping induced both a depression of synaptic currents and an increase of synaptic responsiveness.

From: NMDAR-dependent long-term depression is associated with increased short term plasticity through autophagy mediated loss of PSD-95

Fig. 7

A Representation of the main interactions which define the AMPAR organization/ trapping. PSD-95 can diffuse freely, be slowly mobile and confined into nanodomain when palmitoylated, or be inactivated. AMPAR can be endocytosed, freely mobile at the surface or being trapped by palmitoylated PSD-95 into the domain. Two various kinetic rate constant modifications trigger a synaptic depression, (1) an increase of endocytosis rate, mimicking the initial phase of the NMDAR-dependent LTD and the P2XR-dependent LTD (B). (2) A decrease of the total number of PSD through an increase of their inactivation rate (C), mimicking the depletion of PSD-95 observed during NMDAR-dependent LTD. For each condition, we report in the right panel, the number of open AMPARs during the first glutamate release (mean ± SEM), before (dark dots) and after (color dots) modification of the parameter. A significant decrease of AMPAR response similar to the depression experimentally measured is observed in all conditions. Middle panel, the average traces of the equivalent AMPAR current following 5 glutamate releases at 20 Hz. Right panel, the average of the AMPAR equivalent current following the 5 releases (mean ± SEM), normalized by the initial response. 96 independent simulations are realized in each condition. When depletion of synaptic AMPAR is induced by increasing the endocytosis, there is no modification of simulated paired-pulse ratio while PSD-95 inactivation condition triggers a significant increase of PPR. D Schematic summary of the molecular processes responsible of NMDAR-dependent LTD induction and maintenance. From basal state (left panel), NMDAR activation triggers an increase of endocytosis rate, responsible of the initiation of the depression (middle panel). Then the activation of the GSK3β phosphorylates PSD-95 at T19, targeting it to autophagosomes for degradation. This decrease of traps releases AMPAR out of the PSD, increase the amount of mobile receptors and favoring synaptic responsiveness (left panel).

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