Elsevier

Brain Research

Volume 1249, 16 January 2009, Pages 244-250
Brain Research

Research Report
The effect of mGluR2 activation on signal transduction pathways and neuronal cell survival

https://doi.org/10.1016/j.brainres.2008.10.055Get rights and content

Abstract

In earlier studies, we found profound alterations in specific signal transduction pathways such as mitogen-activated protein kinase signal pathway that mirrored neuronal cell death in Alzheimer disease (AD). To further delineate the mechanism(s) involved in such aberrant signaling, we subsequently showed that mGluR2 is increased in pyramidal neurons in the hippocampus of AD and often co-localizes with neurofibrillary pathology. Based on these data, we suggested that selective neuronal degeneration in AD may arise through the differential expression and activation of specific receptor populations, such as, mGluR2. In this study, to examine the mechanistic relevance of the above-mentioned in vivo findings, we used cell culture models to show that the activation of mGluR2 leads to the activation of extracellular signal-related kinase (ERK) pathways. Importantly, attesting to the in vivo significance of our findings, this pro-survival signaling pathway is also found to be ectopically activated in AD. We also found that the activation of mGluR2 increases the phosphorylation of tau and that the specific activation of mGluR2 reduces oxidative stress mediated cytotoxicity in neuronal cells. Taken together our findings strongly suggest that mGluR2 may participate in mediating the survival of neurons in the face of selective neuronal dysfunction and degeneration in AD. Additionally, our findings lend support to the notion that tau phosphorylation is a neuroprotective antioxidant response to cellular insults.

Introduction

Metabotropic glutamate receptors (mGluRs) have been suggested as therapeutic targets for neurodegenerative diseases since their unique functions allow modulation of signals via G-protein dependent pathways and this may alter neuronal functions more precisely than targeting ionotropic GluRs (iGluRs) (Bruno et al., 2001). In this regard, it is notable that signal transduction by glutamate receptors is mediated by the activation of the MAP kinase pathways (Ferraguti et al., 1999) and that these signal transduction pathways are known to be altered in AD (Webber et al., 2005, Zhu et al., 2003). Additionally, agonists of mGluR lead to an increase in phosphorylated tau mediated through extracellular signal-related kinase (ERK)-mediated kinases and several lines of evidence suggest that the differential expression of glutamate receptors in select populations of neurons accounts for specific neuronal vulnerability (Bruno et al., 2001).

The activation of Group II mGluRs protects neurons against excitotoxic degeneration by the inhibition of glutamate release (Buisson and Choi, 1995, Buisson et al., 1996) such that potent and selective Group II mGluR agonists protect against excitotoxicity in vitro (Kingston et al., 1999) and global ischemia in vivo (Bond et al., 2000). Since mGluR2 appears to play a role in the pathogenesis of neuronal cell death and survival, it is not surprising that mGluR2 is specifically increased in hippocampal neurons in AD (Lee et al., 2004a) and that mGluR2 could play a key role in the pathogenesis of AD (Lee et al., 2004b). In contrast, the expression level of mGluR2 in the dentate gyrus granular neurons is unchanged.

Of interest, the aberrant expression of mGluR2 in the hippocampus is closely associated with phosphorylated tau containing neurofibrillary changes in the pyramidal neurons, which, while traditionally thought of as detrimental (Iqbal and Grundke-Iqbal, 2006), more recently, has been associated with neuronal survival (Lee et al., 2005, Morsch et al., 1999). In the latter, it is notable that the activation of mGluR2 by specific agonists activates the ERK pathway (Ferraguti et al., 1999, Otani et al., 1999), a pro-survival pathway, and that ERK phosphorylates tau at those sites known to be phosphorylated in AD (Reynolds et al., 2000). Based on this, we hypothesized that mGluR2 activation sequentially lead to the activation of the ERK pathway, tau phosphorylation and neurofibrillary pathology in neurons and ultimately neuroprotection. Given the importance of mGluR2 in cellular viability, such neurons are potentially protected from the disease process. To test this hypothesis, in this study, we investigated the effect of mGluR2 activation on cellular viability, ERK activation, and tau phosphorylation in neurons.

Section snippets

The expression of mGluR2 and its effect on ERK in rat primary cortical neurons

While the effect of mGluR2 on ERK pathway activation is known in CHO cells (Ferraguti et al., 1999, Phillips et al., 1998), the expression pattern of mGluR2 has not been examined in primary neurons or other neuronal cell culture models. Since primary neurons or neuronal cell lines such as SHSY5Y cells may provide a more physiologically relevant context to examine the effect of mGluR2 activation, we first determined the expression of mGluR2 protein in rat primary cortical neurons. The membrane

Discussion

In this study, we found that the group II mGluR specific agonist, LY379268, induced ERK activation in rat primary cortical neurons. Moreover, mGluR2 stably transfected cells, which overexpress mGluR2 and do not express mGluR3, showed that ERK activation is specifically mediated by mGluR2 activation. These results demonstrate for the first time that group II mGluR induces ERK activation in primary neuronal cultures and neuronal cell lines in an mGluR2-specific manner. Activation of the ERK

Materials

LY379268, a specific agonist for group II mGluR (EC50mGluR2 = 2.69 nM and EC50mGluR3 = 4.58 nM) was provided by Eli Lilly and Co., Ltd, was dissolved in equimolar NaOH to facilitate solubility. For immunoblot analysis, anti-mGluR2 (Upstate, Lake Placid, NY), anti-phospho-ERK (Cell Signaling, Danvers, MA) and anti-phospho-tau (AT8, Pierce, Rockford, IL) antibodies were used as described previously (Lee et al., 2004a, Perry et al., 1999).

Cell culture

The SHSY5Y human neuroblastoma cell line was cultured in

Acknowledgments

Work in the authors' laboratories is supported by the National Institutes of Health and the Alzheimer's Association.

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