Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Abstract

Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

“…However, other studies, using different models and/or different assays, have obtained results that are not immediately consistent with our observations, suggesting instead a link between GluN2A and ERK1/2 (Kim et al, 2005;Jin and Feig, 2010). On the other hand, the specific link between GluN2B and ERK1/2 activation has been proposed in other studies (Krapivinsky et al, 2003;Chen et al, 2007). The reasons behind these possible discrepancies are unclear.…”

“…Meanwhile, studies addressing the role of NMDAR subunit composition in ERK1/2 signaling pathway in synaptic plasticity and memory have yielded seemingly contrary results. For example, it was reported that GluN2B, but not GluN2A, is associated with RasGRF1 activation (Krapivinsky et al, 2003), and it was demonstrated that GluN2B can block the epilepsy-induced ERK1/2 activation in vivo (Chen et al, 2007). Those studies are consistent with the coupling of GluN2B-containing NMDARs with ERK1/2 activation.…”

Tyrosine Phosphorylation of the 2B Subunit of the NMDA Receptor Is Necessary for Taste Memory Formation

“…The role of tyrosine phosphorylation of NR2B in the association with PSD 95 is less clear. Phosphorylation of NR2A and NR2B and their associated proteins by Src or Fyn was found in some cases to enhance their association with PSD-95 (Rong et al, 2001;Zalewska et al, 2005), whereas under conditions of hypoxia that lead to impaired long-term spatial learning and memory there were marked decreases in the levels of PSD-95-NMDAR complex (Chen et al, 2007). One possible role for the formation of this complex is to protect NR2 subunits from undergoing cleavage by calcium-dependent proteases, and thereby to provide a mechanism for regulating NMDAR expression (Dong et al, 2004).…”

Synaptic Strength Modulation after Cortical Trauma: A Role in Epileptogenesis

“…Although studies performed in slices or cultures have been crucial in uncovering the role of different substances (Graber and Prince, 1999), ionic channels (Desai et al, 1999), and receptors (Chen et al, 2007) in epilepsy, they cannot recreate the complexity of the whole brain, in which different structures interact to maintain the fine balance between excitation and inhibition. To overcome these limitations, we performed the experiments in vivo, to investigate the gradual changes of synaptic efficacy and intrinsic excitability after cortical undercut.…”