MTEP impedes the neuronal polarization and the activity of the Akt–NF‐κB pathway in rat hippocampal neurons

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The establishment of the neuronal polarity requires the morphological and functional differentiation of a somatodendritic and an axonal domain. Studies have identified a number of intracellular and extracellular molecules that are involved in neuronal polarization, such as NGF, BDNF, PI3K/Akt, GSK3, the small GTPases RAS‐related C3 botulinum toxin substrate 1 and cell division control protein 42 homolog, the Par polarity complex, cAMP‐response element‐binding protein, and nuclear factor κB (NF‐κB) (Zhou and Snider, 2006; Hur and Zhou, 2010). However, little is known about the impact of metabotropic glutamate receptors on neuronal polarization. In this study, we engaged in investigating the possible contribution of one of the key metabotropic glutamate receptor isoforms, metabotropic glutamate receptor 5 (mGluR5), in neuronal polarization during the morphological differentiation of developing neurons.
The levels of mGluR5 in the developing rat brain are substantially higher than those in the adult brain (Romano et al., 1996), which implies its possible role in neural development. Both in vitro and in vivo studies have shown that mGluR5 plays a vital role in neuronal survival, differentiation, dendritic morphogenesis, and synaptic plasticity (Catania et al., 2001; Wijetunge et al., 2008; She et al., 2009). In the mixed rat cerebellar cultures, administration of the mGluR5 selective antagonist 2‐methyl‐6‐(phenylethynyl) pyridine (MPEP) reduced the number of granule cells and produced substantial morphological changes in the dendritic trees of Purkinje cells (Catania et al., 2001). Other studies have shown that application of mGluR5 agonist (S)‐3, 5‐dihydroxyphenylglycine to hippocampal neurons contributes to the elongation of dendritic spines (Vanderklish and Edelman, 2002; Abu‐Elneel et al., 2008), and mGluR5 knockout decreases the number of spines (Wijetunge et al., 2008). Furthermore, in vivo study has declared that mGluR5 signaling modulates the formation of the cortical somatosensory circuit (Ballester‐Rosado et al., 2010).
Among a series of potential downstream mediators of mGluR5, PI3K/Akt and NF‐κB were shown to be involved in regulation of neuronal development and plasticity (Corti et al., 2003; Hou, 2004; Shah et al., 2012). More important, Akt and NF‐κB have recently emerged as major regulators of the growth and elaboration of neuronal processes. As a key molecule of PI3K signaling, Akt was reported to regulate the actin organization and cell motility via a novel protein, Girdin (Enomoto et al., 2005). It has also been documented that NF‐κB signaling is involved in axon initiation, elongation, guidance, and branching (Gutierrez et al., 2005; Sanchez‐Ponce et al., 2008; Gutierrez and Davies, 2011). Besides, the activation of PI3K/Akt and NF‐κB signaling pathway were shown to be participated in the neurite extension and neuronal polarity of bone marrow stem cells induced by stem cell factor and granulocyte colony–stimulating factor (Su et al., 2013).
Based on these findings, we hypothesize that mGluR5 is involved in the regulation of neuronal polarity during CNS development. We applied its highly selective antagonist 3‐[(2‐methyl‐4‐thaizolyl) ethynyl] pyridine (MTEP) and agonist (RS)‐2‐chloro‐5‐hydroxyphenylglycine sodium salt (CHPG) to the cultured hippocampal neurons, and observed the polarization of the developing neurons and their axon outgrowth. Given the essential effects of Akt and NF‐kB signaling on neuronal development, we further explored the activation of the Akt and NF‐κB signaling pathway in mGluR5 regulating neuronal polarity.
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