Geon Differential Effects between NR2A and NR2B on Plasticity Memory

 

An NMDA receptor (NMDAR) consists of two NR1 (GluN1) subunits and two additional subunits which are predominately either NR2A (GluN2A) or NR2B (GluN2B). Other subunits, such as GluN3, GluN2C and GluN2D, are relatively rare. Numerous studies have revealed that NR2A- and NR2B-containing NMDARs play distinct roles in memory processes. Some of them are listed below.

  1. NR2A and NR2B play separate roles in the induction of long-term potentiation (LTP) and long-term depression (LTD) (Dalton et al., 2012).
  2. NR2B, not NR2A, has emerged as a central player in addictive behaviors (Hopf, 2017).
  3. Increasing the NR2A/NR2B ratio in neurons of the mouse amygdala inhibits the modification of an existing fear memory trace. (Holehonnur et al., 2016).
  4. During normal development, the expression of NR2B is high at birth but decreases into adulthood, while NR2A expression increases with age (Shipton and Paulsen, 2013).
  5. mGluR5, a protein implicated in addiction, drives the activity-dependent NR2B to NR2A switch (Matta et al., 2011).
  6. Brain-derived neurotrophic factor (BDNF), which has been shown to induce fear extinction (Peters et al., 2010), enhances NR2B-containing NMDAR currents (Otis et al., 2014).

CaMKII binds only to NR2B, not NR2A. This led to the suggestion that the differential effects between the two subunits may arise from their interaction with CaMKII (Shipton and Paulsen, 2013). Since the CaMKII-NR2B binding potentiates synaptic strength (Chapter 5), this notion predicts that NR2B would be responsible for LTP. However, it is not always true for synaptic NMDARs. Many contradictory results about the effects of NR2B on synaptic plasticity have been reported (Shipton and Paulsen, 2013). For extrasynaptc NMDARs in cortical neurons, the opposite was observed: LTD requires the activation of NR2B-containing NMDARs, whereas LTP requires activation of NR2A-containing NMDARs (Massey et al., 2004).

Intriguingly, both tubulin and CRMP2 also interact with NR2B, not NR2A (van Rossum et al., 1999; Brustovetsky et al., 2014). Therefore, only the NR2B-containing NMDARs can be inhibited by tubulin (Chapter 7). While the binding between CaMKII and NR2B does potentiate synaptic strength, CaMKII could dissociate from NR2B, depending on T305/306 phosphorylation (Chapter 6) and possibly other factors. Their dissociation allows tubulin/CRMP2 to bind and inhibit NR2B-containing NMDARs. This may account for the complex influence of NR2B on synaptic plasticity. Furthermore, both NR2A and NR2B are present in the extrasynaptic membrane. The inhibition of NR2B-containing NMDARs by tubulin may suppress neuronal firing via attenuation of NMDA spikes.

In the C-terminal domain of the NR2B subunit, there are three tyrosine residues (abbreviation: Y) which can be phosphorylated by Fyn kinase (Figure 8-1). Phosphorylation at Y1472 prevents NR2B-containing NMDARs from being internalized (Chen and Roche, 2007), consequently increasing their surface expression. Hence, Y1472 is an important regulatory site for neuronal plasticity. BDNF has the capacity to promote Y1472 phosphorylation (Xu et al., 2006).

Image

Figure 8-1. Schematic drawing of the NR2B subunit, highlighting Fyn sites. Phosphorylation at Y1472 by Fyn prevents NR2B-mediated endocytosis, thereby increasing the surface expression of NR2B-containing NMDARs. [Adapted from Wikipedia]

 

Author: Frank Lee
First published: October, 2017