Tyrosine Phosphatases Regulate AMPA Receptor Trafficking during Metabotropic Glutamate Receptor-Mediated Long-Term Depression

Abstract

Two forms of long-term depression (LTD), triggered by activation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), respectively, can be induced at CA1 synapses in the hippocampus. Compared with NMDAR-LTD, relatively little is known about mGluR-LTD. Here, we show that protein tyrosine phosphatase (PTP) inhibitors, orthovanadate and phenylarsine oxide, selectively block mGluR-LTD induced by application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD), because NMDAR-LTD is unaffected by these inhibitors. Furthermore, DHPG-LTD measured using whole-cell recording is similarly blocked by either bath-applied or patch-loaded PTP inhibitors. These inhibitors also block the changes in paired-pulse facilitation and coefficient of variation that are associated with the expression of DHPG-LTD. DHPG treatment of hippocampal slices was associated with a decrease in the level of tyrosine phosphorylation of GluR2 AMPA receptor (AMPAR) subunits, an effect blocked by orthovanadate. Finally, in dissociated hippocampal neurons, orthovanadate blocked the ability of DHPG to reduce the number of AMPA receptor clusters on the surface of dendrites. Again, the effects of PTP blockade were selective, because NMDA-induced decreases in surface AMPAR clusters was unaffected by orthovanadate. Together, these data suggest that activation of postsynaptic PTP results in tyrosine dephosphorylation of AMPARs and their removal from the synapse.

Interaction between Ephrins and mGlu5 Metabotropic Glutamate Receptors in the Induction of Long-Term Synaptic Depression in the Hippocampus

“…Activated ephrins trigger a cascade of phosphorylation processes mediated by soluble tyrosine kinases (see Introduction and references therein). Tyrosine phosphorylation is known to affect AMPA receptor trafficking and responses, thereby influencing the efficacy of excitatory synaptic transmission (Wang et al, 2005;Moult et al, 2006). The intrinsic ephrin-B component might be critical for the duration of synaptic depression providing that mGlu5 receptors are endogenously activated (or constitutively active).…”

“…In addition, clustered EphB1/Fc still induced LTD in the presence of the PI-3-K inhibitor, LY49002, and induced a trend to a long-lasting depression of synaptic transmission in the presence of the MEK inhibitor, UO126. It should be highlighted that multiple signaling pathways contribute to DHPG-induced synaptic depression at the Schaffer collateral-CA1 synapses, including activation of c-Jun N-terminal kinases (Li et al, 2007), p38 MAPK (Rush et al, 2002), nuclear factor B (O'Riordan et al, 2006), tyrosine dephosphorylation (Moult et al, 2002(Moult et al, , 2006Gladding et al, 2009). Which of these pathways mediates the synergism between ephrin-B2 and mGlu5 receptors on synaptic transmission remains to be determined.…”

The rat perirhinal cortex: A review of anatomy, physiology, plasticity, and function

“…Furthermore, transgenic overexpression of the NR2B subunit in hippocampal and cortical neurons enhances performance in an object recognition task yet does not promote LTD in the area CA1 (Wang et al, 2009) which is a conflicting finding compared to the majority of research in this area. There are a large number of molecular mechanisms involved in object recognition memory that are correlated with LTD including L-type voltage-dependent Ca 2+ channels (Seoane et al, 2009), CREB (Warburton et al, 2005), muscarinic cholinergic receptors (Warburton et al, 2003;Massey et al, 2008), GABA receptors (Wan et al, 2004) mGlu receptors (Barker et al, 2006a;Moult et al, 2006), NMDA receptors (Cho et al, 2000Roberts et al, 2009;, kainate receptors (Barker et al, 2006a;Park et al, 2006;Holman et al, 2007) and AMPA receptor internalisation (Griffiths et al, 2008). Therefore, although both LTP and LTDlike processes might be involved in object recognition memory, it would appear that an LTD-like process is the principle physiological mechanism underlying recognition memory.…”

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

“…In contrast, the effect of the more selective Ro 25-6981 on the acquisition of conditioned fear or synaptic plasticity in the amygdala is currently unknown. In addition, AMPA receptor endocytosis occurs downstream of NMDA receptor activation in the induction of LTD (Ahmadian et al, 2004;Mangiavacchi and Wolf, 2004;Moult et al, 2006). Accordingly, activation of NMDA NR2B receptors would be expected to affect a number of different cellular processes, in addition to mediating AMPA receptor endocytosis.…”