Interaction Between  CaMKII and GluN2B Controls ERK-Dependent Plasticity

Abstract

Understanding how brief synaptic events can lead to sustained changes in synaptic structure and strength is a necessary step in solving the rules governing learning and memory. Activation of ERK1/2 (extracellular signal regulated protein kinase 1/2) plays a key role in the control of functional and structural synaptic plasticity. One of the triggering events that activates ERK1/2 cascade is an NMDA receptor (NMDAR)-dependent rise in free intracellular Ca 2ϩ concentration. However the mechanism by which a short-lasting rise in Ca 2ϩ concentration is transduced into long-lasting ERK1/2-dependent plasticity remains unknown. Here we demonstrate that although synaptic activation in mouse cultured cortical neurons induces intracellular Ca 2ϩ elevation via both GluN2A and GluN2B-containing NMDARs, only GluN2B-containing NMDAR activation leads to a long-lasting ERK1/2 phosphorylation. We show that ␣CaMKII, but not ␤CaMKII, is critically involved in this GluN2B-dependent activation of ERK1/2 signaling, through a direct interaction between GluN2B and ␣CaMKII. We then show that interfering with GluN2B/␣CaMKII interaction prevents synaptic activity from inducing ERKdependent increases in synaptic AMPA receptors and spine volume. Thus, in a developing circuit model, the brief activity of synaptic GluN2B-containing receptors and the interaction between GluN2B and ␣CaMKII have a role in long-term plasticity via the control of ERK1/2 signaling. Our findings suggest that the roles that these major molecular elements have in learning and memory may operate through a common pathway.

Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B

“…When activated, NMDA receptors exhibit a relatively higher permeability to Ca 2+ ion than the AMPA or kainite excitatory receptors [24]. NMDA receptors are functionally linked to a variety of normal neuronal processes, including neural development, plasticity, learning, and memory [25–27]. However, with excessive Ca 2+ influx, NMDA receptors are implicated in neuropathological conditions, such as excitotoxicity and many neurodegenerative diseases [28].…”

“…Upon activation, GluN1/GluN2B receptors allow for the entry of large amounts of cations, particularly Ca 2+ , which is responsible for its functional role in neuronal plasticity, especially long term potentiation, as well as its role in learning and memory [25, 27]. When activated in excess, however, the GluN1/GluN2B receptors are implicated in excitotoxicity and cell death [40].…”

A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior

“…Postsynaptic density fractions (PSDs) were prepared as previously described 23 from treated 15 days in vitro hippocampal cell cultures. In brief, cells were harvested and processed for successive centrifugation steps in specific cold buffers to separate PSD from the non-PSD.…”

N-Methyl-D-Aspartic Acid Receptor Activation Downregulates Expression ofδSubunit-Containing GABAAReceptors in Cultured Hippocampal Neurons

“…An interaction between the NR2B subunit of NMDARs and CaMKII or RasGRF1 may lead to ERK1/2 activation (Kurino et al, 1995;Krapivinsky et al, 2003;El Gaamouch et al, 2012). It is noteworthy that activation of CaMKII was not necessary for the NMDA effects on d subunit expression.…”