Long-term potentiation persists in an occult state following mGluR-dependent depotentiation

Depotentiation, the reversal of long-term potentiation (LTP), can be induced by activation of metabotropic glutamate receptors (mGluRs) or NMDA receptors (NMDARs). Although NMDAR-dependent depotentiation is due to a protein phosphatase-dependent erasure of LTP, the notion that rnGluR-dependent depotentiation also involves LTP erasure is controversial. To address this issue we used electrophysiological and biochemical approaches to investigate mGluR-dependent depotentiation in hippocanipal slices. Activating group I mGluRs with (R,S)-3,5-dihydroxyphenylglycine (DHPG) induced robust depotentiation in both the CAI and CA3 regions of hippocarnpal slices. Western immunoblotting of samples prepared from DHPG-treated slices revealed, however, that activation of group I mGluRs causes a transient increase in phosphorylation of AMPA receptor GluRl subunits at sites crucial for LTP and under sonic conditions causes persistent activation of alpha CamKII. The paradoxical ability of DHPG to induce depotentiation while at the same time activating signaling pathways involved in LTP suggests that LTP might not be erased by mGIuR-dependent depotentiation. Consistent with this, DHPG-induced depotentiation did not restore the ability of high-frequency stimulation to induce LTP at synapses that had previously undergone saturating levels of LTP. In addition, blocking the expression of DHPG-induced LTD revealed hidden LTP Lit depotentiated synapses. Our results indicate that LTP and mGluR-dependent LTD can co-exist at excitatory synapses. (c) 2005 Elsevier Ltd. All rights reserved.