Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal‐regulated kinases (ERK) activity in cultured rat hippocampal neurons

Abstract

The extracellular signal-regulated kinases (ERK) signalling cascade is a key pathway that mediates the NMDA receptor (NMDAR)-dependent neuronal plasticity and survival. However, it is not clear yet how NMDARs regulate ERK activity. Stimulation of the NMDARs induces a complex modification of ERK that includes both ERK activation and inactivation and depends on particular experimental conditions. Here we show that there exists a differential restriction in the regulation of ERK activity that depends on the pool of NMDAR that was activated. The synaptic pool of NMDARs activates ERK whereas the extrasynaptic pool does not; on the contrary, it triggers a signalling pathway that results in the inactivation of ERK. As a result, simultaneous activation of both extrasynaptic and synaptic NMDAR using bath application of NMDA or glutamate (a typical protocol explored in the majority of studies) produced ERK activation that depended on the concentration of agonists and was always significantly weaker than those mediated by synaptic NMDARs. Since the activation of the extrasynaptic NMDA is attributed mainly to global release of glutamate occurring at pathological conditions including hypoxic/ischaemic insults, traumas and epileptic brain damage, the reported differential regulation of ERK cascade by NMDARs provides a unique mechanism for an early identification of the physiological and/or pathophysiological consequences of NMDAR activation. The negative regulation of the ERK activity might be one of the first signalling events determining brain injury and constitutes a putative target of new pharmacological applications. The NMDA subtype of glutamate receptors (NMDAR) is a key receptor involved in the regulation of multiple processes related to synaptic plasticity including learning, memory, neuron development, spine formation, long-term potentiation (LTP) and long-term depression (LTD). The mechanisms underlying such diversity of neuronal responses to the activation of a single receptor are not known. At least some of these processes are associated with the NMDA-dependent activation of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK) signalling cascade whose inhibition modifies spine formation, long-term memory, LTP and cell survival (Adams & Sweatt, 2002;Hardingham & Bading, 2003;Goldin & Segal, 2003;Thomas & Huganir, 2004). Stimulation of NMDA receptors by specific agonists (Bading & Greenberg, 1991;Kurino et al. 1995) or via an increase of synaptic A. Ivanov and C. Pellegrino contributed equally to this work. activity (Hardingham et al. 2001) results in strong ERK phosphorylation. On the other hand, applications of the high concentrations of NMDA (70-100 μm) to neuronal cultures provokes a complex effect; it induces both activation and inactivation of ERK (Chandler et al. 2001;Kim et al. 2005). Although different suggestions were put forward to explain the complex effects of NMDAR agonists on ERK activity (Chandler et al. 2001;Kim et al. 2005), none of them provided compelling evidence supporting their hypo...

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

“…Synaptic vs extrasynaptic location of NMDARs critically alters receptor function and signaling pathway activation (Groc et al, 2009;Hardingham and Bading, 2010;Hardingham et al, 2002;Ivanov et al, 2006;Lau and Zukin, 2007). Extrasynaptic NR2B-containing NMDARs regulate NR2A function, potentially altering synapse development and plasticity (Kollen et al, 2008;Zhu et al, 2005).…”

Platelet-derived Growth Factor Selectively Inhibits NR2B-containing N-Methyl-D-aspartate Receptors in CA1 Hippocampal Neurons

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