Age-related impairment of declarative memory: linking memorization of temporal associations to GluN2B redistribution in dorsal CA1.

Alice Shaam Al Abed,Nathalie Sans,Azza Sellami,Eva‐Gunnel Ducourneau,Peter Vanhoutte,Aline Marighetto,Laurent Brayda‐Bruno,Catherine Bennetau‐Pelissero,Pierre Trifilieff,Mylene Potier,Aline Desmedt,Pauline Gerbeaud‐Lassau,Valerie Lamothe

doi:10.1111/acel.13243

Abstract

GluN2B subunits of NMDA receptors have been proposed as a target for treating age‐related memory decline. They are indeed considered as crucial for hippocampal synaptic plasticity and hippocampus‐dependent memory formation, which are both altered in aging. Because a synaptic enrichment in GluN2B is associated with hippocampal LTP in vitro, a similar mechanism is expected to occur during memory formation. We show instead that a reduction of GluN2B synaptic localization induced by a single‐session learning in dorsal CA1 apical dendrites is predictive of efficient memorization of a temporal association. Furthermore, synaptic accumulation of GluN2B, rather than insufficient synaptic localization of these subunits, is causally involved in the age‐related impairment of memory. These challenging data identify extra‐synaptic redistribution of GluN2B‐containing NMDAR induced by learning as a molecular signature of memory formation and indicate that modulating GluN2B synaptic localization might represent a useful therapeutic strategy in cognitive aging.

Highlights

The episodic component of declarative memory (DM), that is, our capability to remember conjunctions of what happened where and when, undergoes preferential degradation during aging
Our work unveils an unexpected trafficking of hippocampal N-methyl-d-aspartate receptors (NMDAR) during memory formation by showing post-learning rearrangements of GluN2A/B subunits that differ from the ones associated with long-term potentiation (LTP) in vitro
For Golgi analyses, all groups (n = 4 young + vehicle, n = 3 aged + vehicle, and n = 3 aged + 1 μM E2) underwent both stages of the radial maze task and were prepared 24 h later for Golgi staining. (c) Effects of age and treatment on the learning-induced activation of an ensemble of memory-related areas. c-Fos positive cells were counted in the dorsal hippocampus, pre-frontal cortex (Pre-Limbic, PrL and Infra-Limbic, IL), Anterior Cingulate Area (ACA); Dorso-Medial Striatum (DMS) and Lateral Entorhinal Cortex (LEC)

Summary

| INTRODUCTION

The episodic component of declarative memory (DM), that is, our capability to remember conjunctions of what happened where and when, undergoes preferential degradation during aging. We directly tackled this question in mice by focusing on a crucial component of declarative memory formation: the dorsal (d) CA1-dependent memorization of temporal associations, which is degraded in aging (Sellami et al, 2017). We manipulated synaptic localization of GluN2 subunits by modulating their interaction with PSD-95 (Niethammer et al, 1996) using a TAT interfering peptide (Aarts et al, 2002). These correlative and interventional molecular approaches were combined to behavioral assessments of memory for temporal associations in young and aged mice

| RESULTS

| DISCUSSION

| EXPERIMENTAL PROCEDURES

Findings

| Behavioral procedure