Glutamate receptors are involved in synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Three groups studied how changes in the distribution and phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors were related to synaptic activity and plasticity. Ehlers showed that endocytosis and recycling of AMPA receptors were dependent on the type of stimulation in cultured cortical neurons and found that, if AMPA receptors were stimulated directly, they were internalized and sorted from early endosomes to the lysosome for degradation. If the neurons were stimulated by agonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor, then the AMPA receptors were endocytosed and recycled to the synaptic regions of the plasma membrane via a mechanism that required Ca2+-dependent dephosphorylation of a consensus protein kinase A site and subsequent rephosphorylation by protein kinase A. Heynen et al. found that, in the hippocampus of adult rats in which LTP had been induced, there was an increase in the amount of AMPA receptor subunits in synaptic membranes and that, in the hippocampus of adult rats in which LTD had been induced, there was a decrease in the abundance of AMPA receptors and NMDA receptors in synaptic membranes. These changes were dependent on NMDA receptor activity and were reversible, i.e., if LTP was induced and then LTD was caused in the same animal in the same region, then the levels of the glutamate receptors decreased and vice versa. Xia et al. studied changes in the AMPA glutamate receptor 2 (GluR2) subunit in response to the induction of LTD in cultured cerebellar Purkinje cells. LTD was blocked by the perfusion of peptides that inhibited the ability of the GluR2 subunit to interact with the protein kinase C-interacting protein (PICK1) (which binds to a PDZ-binding motif in the COOH-terminus of the GluR2 when it is phosphorylated by protein kinase C). Furthermore, LTD was inhibited if clathrin-mediated endocytosis was blocked, suggesting that the protein kinase C phosphorylation and PICK1 interaction with the GluR2 may promote endocytosis of the AMPA receptor during LTD.
Ehlers, M.D. (2000) Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28: 511-525. [Online Journal]
Heynen, A. J., Quinlan, E. M., Bae, D.C., and Bear, M.F. (2000) Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo. Neuron 28: 527-536. [Online Journal]
Xia, J., Chung, H.J., Wihler, C., Huganir, R.L., and Linden, D.J. (2000) Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ-domain-containing proteins. Neuron 28: 499-510. [Online Journal]