Protein phosphatase inhibitors facilitate DHPG‐induced LTD in the CA1 region of the hippocampus

Abstract

1 We have shown earlier that activation of metabotropic glutamate (mGlu) receptors using a group I-speci®c mGlu receptor agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus. In an attempt to determine the signal transduction mechanisms involved in this form of synaptic plasticity, we have tested the eects of a range of inhibitors on DHPG-induced LTD. 2 In vitro grease-gap electrophysiological recordings were performed in the rat hippocampal CA1 region. 3 We have found that DHPG-induced LTD is resistant to the two potent protein kinase C (PKC) inhibitors, GoÈ 6976 (10 mM) and GoÈ 6983 (10 mM), the potent and selective protein kinase A (PKA) inhibitor, KT 5720 (10 mM), and the potent broad spectrum kinase inhibitor, staurosporine (10 mM). 4 In contrast, non-selective inhibitors of protein phosphatases (PP1 and PP2A), okadaic acid (1 mM) or calyculin A (1 mM), facilitated DHPG-induced LTD. However, an inhibitor of protein phosphatase 2B, FK 506 (1 mM), did not in¯uence this process. 5 The PP1/PP2A protein phosphatase inhibitors, but none of the other agents tested, also inhibited (S)-a-methyl-4-carboxyphenylglycine (MCPG)-induced reversal of DHPG-induced LTD. 6 These data suggest that activation of neither PKC nor PKA is involved in DHPG-induced LTD. They do, however, suggest that the process is under regulation by protein phosphorylation and dephosphorylation.

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

“…Our present observation that direct loading of a single neuron with either of these inhibitors is as effective as bath application strongly suggests that the critical PTP(s) associated with DHPG-LTD is located postsynaptically. The present study uses female rats, because our original description of DHPG-LTD (Palmer et al, 1997) and its subsequent characterization (Palmer et al, 1997;Schnabel et al, 2001;Moult et al, 2002;Rammes et al, 2003) were conducted using this sex. Although studies on male animals have reached broadly similar conclusions (Watabe et al, 2002;Rammes et al, 2003;Huang et al, 2004), it should be born in mind that possible sex linked differences could exist.…”

“…DHPG-LTD does not occlude with NMDAR-LTD (Palmer et al, 1997;Fitzjohn et al, 1999;Huber et al, 2001) and is independent of Ca 2ϩ ) and serine/threonine phosphatases (Schnabel et al, 2001), indicating a very different underlying mechanism. DHPG-LTD involves activation of G-proteins (Watabe et al, 2002;Huang et al, 2004), protein tyrosine phosphatases (PTPs) (Moult et al, 2002), mitogen-activated protein kinase (MAPK) cascades (Gallagher et al, 2004;Huang et al, 2004), and postsynaptic protein synthesis (Huber et al, 2000).…”

Coactivation of M1Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

“…Although Src has been implicated in fewer hippocampal plasticities, its activation is required for HFS-LTP (Lu al., 1998;Salter, 1998). Interestingly, agonist induced mGluR LTD, which can be blocked by simultaneously inhibiting mGluR1 and mGluR5 receptors (Volk et al, 2006), requires ERK activation, which does not require the PLC pathway (Fitzjohn et al, 2001;Schnabel et al, 2001;Gallagher et al, 2004), and it was reported previously that neuronal mGluR5 activation of ERK requires Src (Mao et al, 2005). Thus, activation of Src kinase and ERK appears to be a mechanism shared by several different G␣q-coupled receptors to induce multiple forms of long-term synaptic plasticity.…”

Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus

“…To test this, we first monitored the LTD in fEPSPs induced by DHPG (100 M, 10 min) in stratum radiatum of CA1. DHPG at 50 -100 M has previously been shown to induce a robust LTD that is rapid in onset, specific to Group I mGluR activation, and NMDAR independent Schnabel et al, 2001;Huang and Hsu, 2006). In this experiment, we routinely recorded the responses to paired-pulse stimuli (50 ms interstimulus interval) throughout each experiment to look for presynaptic changes in transmitter release probability.…”