Long-term depression: Receptors and expression mechanisms

Activity-dependent changes in synaptic strength, the leading cellular candidate of memory formation, are induced by patterns of synaptic activity that leads to the activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors or Group I metabotropic glutamate receptors (mGlur). Strong activation of the NMDA receptors induces long-term potentiation (LTP) where modest stimulations lead to long-term depression (LTD) of synaptic strength. While NMDA receptors bidirectionaly regulate synaptic strength, activation of mGlu receptors only induces LTD of synaptic transmission. Despite the significant advances in the understanding of the molecular mechanism of synaptic plasticity there is no cohesive model of LTD in the hippocampus. In this thesis I explore differences in expression mechanisms between mGlur-dependent LTD and NMDAR-dependent LTD. I present results combining electrophysiology, pharmacology, and biochemistry techniques to test how activation of the mGlu and NMDA receptors alter the phosphorylation of different sites in the GluR1 subunit of the AMPA receptor. I choose the GluR1 subunit of the AMPA receptors for its role in the expression of activity-dependent changes of synaptic transmission.; I first present the results of experiments examining how the expression mechanisms of an established LTP are affected by activation of mGlur-dependent depotentiation. I found that post LTP activation of mGlur strongly depotentiates LTP, however, the expression mechanisms of LTP are unaltered by mGlur-dependent "depotentiation". While mGlur activation cause strong phosphorylation of S845 and S831 in the GluR1 subunit of the AMPA receptors, NMDA receptors activation lead to strong dephosphorylation of S845, a site strongly dephosphorylated during LTD. I found strong dephosphorylation of S845 following stimulations that did not induce LTD whereas dephosphosphorylation of T840, a novel phosphorylation in the GluR1 subunit, was strongly dephosphorylated during conditions that induced LTD. Lastly, I present preliminary results of experiments testing the effects of low frequency stimulation (LFS) at the Schaffer Collateral (SC) to CA1 synapse. I found that during US there are strong alterations in inhibitory and excitatory synaptic transmission that seem to be critical for the induction of LTD. I hope these results may add a new perspective to current models of LTD at the Schaffer Collateral to CA1 synapse.