Expression of N-methyl D-aspartate (NMDA) receptordependent homosynaptic long term depression at synapses in the hippocampus and neocortex requires the persistent dephosphorylation of postsynaptic protein kinase A substrates. An attractive mechanism for expression of long term depression is the loss of surface AMPA (␣-amino-3-hydroxy-5-methylisoxazale-4-propionate) receptors at synapses. Here we show that a threshold level of NMDA receptor activation must be exceeded to trigger a stable loss of AMPA receptors from the surface of cultured hippocampal neurons. NMDA also causes displacement of protein kinase A from the synapse, and inhibiting protein kinase A (PKA) activity mimics the NMDA-induced loss of surface AMPA receptors. PKA is targeted to the synapse by an interaction with the A kinase-anchoring protein, AKAP79/150. Disruption of the PKA-AKAP interaction is sufficient to cause a long-lasting reduction in synaptic AMPA receptors in cultured neurons. In addition, we demonstrate in hippocampal slices that displacement of PKA from AKADs occludes synaptically induced long term depression. These data indicate that synaptic anchoring of PKA through association with AKAPs plays an important role in the regulation of AMPA receptor surface expression and synaptic plasticity.
Hippocampal long term synaptic depression (LTD)1 is induced by appropriate activation of postsynaptic NMDA receptors (1) and is expressed by a reduction in AMPA receptormediated currents (2). Dephosphorylation of postsynaptic protein kinase A (PKA) substrates appears to be both necessary and sufficient for expression of LTD in area CA1 of the hippocampus. For example, postsynaptic inhibition of PKA depresses synaptic transmission and occludes LTD (3) and reversal of LTD with high frequency synaptic stimulation (dedepression) is selectively blocked by PKA inhibitors (4). In addition, LTD correlates with the persistent (Ͼ1 h) dephosphorylation of a PKA site on AMPA receptors, Ser 845 of the GluR1 subunit (4, 5). Dephosphorylation of Ser 845 decreases AMPA receptor-mediated currents (6, 7) and is therefore likely to contribute directly to LTD expression.It is now clear that another consequence of NMDA receptor activation is clathrin-mediated endocytosis of AMPA receptors (8 -11). Although these data strongly suggest that AMPA receptor internalization also contributes to the expression of LTD, several questions remain. First, it is surprising to note that NMDA receptor activation has not yet been shown to cause a stable long term reduction in surface-expressed AMPA receptors. In fact, the work from Ehlers (10) shows that NMDA receptor activation causes only a transient internalization of AMPA receptors (10). For LTD to be expressed by a reduction in the number of AMPA receptors, it must be possible for NMDA receptor activation to trigger a persistent change. Second, it is not clear what role dephosphorylation of PKA substrates plays in this process. Several findings suggest that the state of phosphorylation of Ser 845 of GluR1 may regulate its surfa...
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