Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats.

Yan-Yan Sun,Jie Yu,Shu-Su Liu,Min Zhuo,Xue-Han Zhang,Bao-Ming Li,Wei Cai

doi:10.1038/srep30743

Abstract

The number and subtype composition of N-methyl-d-aspartate receptor (NMDAR) at synapses determines their functional properties and role in learning and memory. Genetically increased or decreased amount of GluN2B affects hippocampus-dependent memory in the adult brain. But in some experimental conditions (e.g., memory elicited by a single conditioning trial (1 CS-US)), GluN2B is not a necessary factor, which indicates that the precise role of GluN2B in memory formation requires further exploration. Here, we examined the role of GluN2B in the consolidation of fear memory using two training paradigms. We found that GluN2B was only required for the consolidation of memory elicited by five conditioning trials (5 CS-US), not by 1 CS-US. Strikingly, the expression of membrane GluN2B in CA1was training-strength-dependently increased after conditioning, and that the amount of membrane GluN2B determined its involvement in memory consolidation. Additionally, we demonstrated the increases in the activities of cAMP, ERK, and CREB in the CA1 after conditioning, as well as the enhanced intrinsic excitability and synaptic efficacy in CA1 neurons. Up-regulation of membrane GluN2B contributed to these enhancements. These studies uncover a novel mechanism for the involvement of GluN2B in memory consolidation by its accumulation at the cell surface in response to behavioral training.

Highlights

The N-methyl-D-aspartate receptor (NMDAR) is widely known to be the synaptic coincidence detector that is required for certain types of learning[1,2] and essential for controlling synaptic plasticity[3] and gating memory formation[4,5,6,7,8]
Post hoc analysis confirmed that the larger N-methyl-d-aspartate receptor (NMDAR)-EPSC amplitudes and decay times were blocked by ifenprodil in the five CS-US conditioned group compared with the other two groups (p < 0.05), which is the same result that was found for the single CS-US conditioned group compared with the control group (p < 0.05; Fig. 5F), suggesting the increased GluN2B incorporating into synaptic sites and functioning. These results indicated that the up-regulation of membrane GluN2B after fear conditioning enhanced NMDAR-mediated synaptic response in CA1 pyramidal neurons, consistent with the studies on genetic mice[8,30]
To examine whether an increased amount of membrane GluN2B-containing NMDARs contributes to neuronal excitability, we examined the effect of ifenprodil on the action potential (AP) number

Summary

Introduction

The N-methyl-D-aspartate receptor (NMDAR) is widely known to be the synaptic coincidence detector that is required for certain types of learning[1,2] and essential for controlling synaptic plasticity[3] and gating memory formation[4,5,6,7,8]. Accumulating evidence indicates that the number of GluN2A and GluN2B subtypes changes following synaptic plasticity[17] and sensory experience[19,20,21]. In addition to these well-described changes within mature synapses, emerging evidence suggests that GluN2A or GluN2B expression in the adult cortex and hippocampus can be dynamically modulated by individual experiences (i.e., enriched environment or social interactions)[22,23]. Requirement of GluN2B for memory consolidation depended on the amount of GluN2B on the cell surface These results provide a new insight regarding the role of the GluN2B subtype in memory formation

Methods

Results

Conclusion