Ampa Receptor Endocytosis And Removal From Synapses

The controlled endocytic removal of AMPARs from synapses is as important for synaptic function and plasticity as the delivery of new AMPARs. Similar to the constitutive and regulated pathways for synaptic delivery, there are also constitutive and regulated pathways for the trafficking of AMPARs out of synapses. The continuous movement of receptors from the synaptic membrane into extrasynaptic compartments was originally hypothesized from the fast run-down of AMPAR-mediated synaptic transmission when interfering with the exocytic machinery or with the specific interaction between NSF and GluR236. These experiments have now been corroborated and extended with molecular studies establishing that the GluR2-GluR3 population of AMPARs continuously cycle in and out of synapses, as mentioned earlier. Although the mechanisms for this cycling are unknown, NSF might play a critical role in this process by regulating the interactions between GluR2 and PICK137.

In addition to the continuous movement of AMPARs out of synapses, there is also ample evidence for the activity-dependent removal of receptors, which leads to long-lasting depression of synaptic strength (i.e., LTD). In contrast with the clear subunit-specific pathways for receptor delivery, it is still discussed which AMPAR populations are affected by this regulated removal. Hippocampal neurons lacking both GluR2 and GluR3 subunits can undergo normal LTD60, suggesting that at least GluR1-containing receptors are subject to regulated removal. On the other hand, a switch of GluR2 binding partners from GRIP1 to PICK1 accompanies LTD61,62, suggesting that the GluR2 subunits is critical for LTD. In fact, there is evidence that AMPAR removal during LTD may affect all AMPAR populations. This has been demonstrated in dissociated neuronal cultures, where the endocytosis of different receptor subunits can be directly monitored63,64. More recently, it has been found that Rab5 is the critical Rab protein that mediates AMPAR removal during LTD in hippocampal slices41. Interestingly, Rab5 is able to remove all AMPAR populations from synapses41, suggesting that LTD affects all AMPAR subunits also in slices.

Still, subunit-specific internalization pathways do exist, as it has been described for GluR2-specific endocytosis and redistribution after internalization in hippocampal neurons64-66. Also, it is well established that PKC phosphorylation of GluR2 at Ser880 is correlated with LTD in the hippocampus and cerebellum62,67. The most accepted model for this regulated removal involves the preferential interaction of unphosphorylated GluR2 with GRIP1, which would favor the presence of the receptor at the synapse. After phosphorylation by PKC, GluR2 would dissociate from GRIP1 and bind PICK1, and this new interaction would retain GluR2 away from synapses37. This interplay of GluR2 interactions with GRIP1 and PICK1 has been reinforced with the finding that GRIP1 and PICK1 also interact directly68.

It is also well established that LTD correlates with GluR1 dephosphorylation in the hippocampus48,69, and that phosphatase activity is required for AMPAR removal and LTD expression63,64,70,71. These results suggest that phosphatase activity and GluR1 dephosphorylation are triggering events for AMPAR endocytic removal. However, it has also been proposed that GluR1 dephosphorylation occurs downstream of AMPAR endocytosis, and it is required to retain the receptor away from the synapse and prevent its reinsertion41. In fact, this interpretation is consistent with the original observation that phosphatase activity is required for LTD maintenance71.

The subcellular organization of the endocytic machinery for the synaptic removal of AMPARs is not fully established yet, but some morphological and molecular studies have provided important clues. Multiple experimental observations indicate that there are endocytic "hotspots" at the extrasynaptic edges of the postsynaptic membrane72, suggesting that these could be the gates for AMPAR endocytosis73. In support of this scenario, the endocytic protein Rab5 is also clustered at extrasynaptic sites laterally from the postsynaptic membrane41. As mentioned above, Rab5 drives AMPAR removal during LTD41. Rab5 is involved in clathrin-dependent endocytosis, and therefore, its role in AMPAR endocytosis during LTD is in good agreement with the established observation that AMPAR removal during LTD is mediated by clathrin-dependent mechanisms66,74. Interestingly, most Rab5 is present in its inactive configuration (GDP-bound) in basal conditions in the hippocampus. However, upon NMDAR activation, Rab5-GTP accumulates rapidly and transiently41. These results suggest a model in which LTD induction triggers the activation of Rab5 at pre-established endocytic hotspots, which in turn produces a transient endocytic wave, resulting in the synaptic removal of AMPARs. An important new aspect of this model is that the endocytic machinery does not act as a passive mediator of AMPAR removal, but as a regulated component in the signaling cascade that underlies LTD.

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