Functional dynamics of cortical NMDA receptors during systems-level memory consolidation and forgetting
Defended on March 31, 2016
PhD supervisor: Olivier Nicole, IMN CNRS 5293.
Initially encoded in the hippocampus, new declarative memories are thought to become progressively dependent on a broadly distributed cortical network as they mature and consolidate over time. Whereas we have a good understanding of the mechanisms underlying the formation of new memories in the hippocampus, little is known about the cellular and molecular mechanisms by which recently acquired information is transformed into remote memories at the cortical level. The N-methyl-D-aspartate receptor (NMDAR) is widely known to be a key player in many aspects of long-term experience-dependent synaptic changes underlying associative memory processes. Based on their distinct biophysical properties, we postulated that the activity-dependent surface dynamics of the two predominant GluN2 subunits (GluN2A and GluN2B) of NMDARs present in the adult neocortex could provide a metaplastic control of synaptic plasticity supporting the progressive embedding and stabilization of long‐lasting associative memories within cortical networks during memory consolidation.
By combining, in adult rats, behavioral, biochemical, pharmacological and innovative strategies consisting in manipulating trafficking of NMDAR subunits at the cell membrane, our results identify a cortical switch in the synaptic GluN2-containing NMDAR composition which drives the progressive embedding and stabilization of long-lasting memories within cortical networks. We first established that cortical GluN2B-containing NMDARs and their specific interactions with the synaptic signaling CaMKII protein are preferentially recruited upon encoding of associative olfactory memories to enable neuronal allocation, the process via which a new memory trace is thought to be allocated to a given neuronal network.
As these memories are progressively processed and embedded into cortical networks, we observed a learning-induced surface redistribution of cortical GluN2B-containing NMDARs outwards or inwards synapses which respectively drives the progressive stabilization and subsequent forgetting of remote memories over time. Finally, increasing the strength, upon encoding, of the initial memory leads to a faster increase of the cortical GluN2A/GluN2B synaptic ratio and accelerates the kinetics of hippocampal–cortical interactions, which translated into a faster stabilization of memories within cortical networks.
Taken together, our results provide evidence that GluN2B‐NMDAR surface trafficking controls the fate of remote memories (i.e. stabilization versus forgetting), shedding light on a novel mechanism used by the brain to organize recent and remote memories.
Keywords : Systems-level consolidation – Remote associative memory – NMDA receptor – Cortical network – Hippocampus – Synaptic plasticity – Surface dynamics – Memory allocation – Forgetting.
Publications :Bessières B, Bontempi B, Nicole O (2013). Tiny light, big hope. Movement Disorders 28(9):1210.
Bessières B, Giacinti A, Nicole O, Bontempi B. Assessing recent and remote associative olfactory memory in rats using the social transmission of food preference paradigm. En préparation.
Nathalie SANS, Présidente, Neurocentre Magendie, INSERM U862, Université de Bordeaux
Serge LAROCHE, Rapporteur, Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Université Paris-Sud
Gaël MALLERET, Rapporteur, Centre de Recherche en Neurosciences de Lyon, INSERM U1028, Université Lyon
Cédrick FLORIAN, Examinateur, Centre de Recherches sur la Cognition Animale, CNRS UMR 5169, Université Toulouse 3
Jacques MICHEAU, Examinateur, INCIA, CNRS UMR 5287, Université de Bordeaux
Olivier NICOLE, Directeur de thèse, IMN, CNRS UMR 5297, Université de Bordeaux
Bruno BONTEMPI, Invité, IMN, CNRS UMR 5297, Université de Bordeaux