Memory Susceptibility to Retroactive Interference Is Developmentally Regulated by NMDA Receptors

Abstract

Graphical AbstractHighlights d LTP in the dentate gyrus becomes more readily reversible during development d The age dependence of depotentiation is controlled by the GluN2A/GluN2B subunit ratio d The developmental enhancement of LTP reversal is associated with increased forgetting d Changes in the GluN2A/GluN2B subunit ratio affect rates of forgetting In BriefGe et al. report that the NMDA receptor GluN2A/GluN2B subunit ratio determines the sensitivity of strengthened neuronal connections to depotentiation. As the ratio rises during development, memories become more vulnerable to disruption by post-learning interference. These findings help to illuminate the mechanism by which forgetting rates may vary with age. SUMMARYRetroactive interference (RI) occurs when new incoming information impairs an existing memory, which is one of the primary sources of forgetting. Although long-term potentiation (LTP) reversal shows promise as the underlying neural correlate, the key molecules that control the sensitivity of memory circuits to RI are unknown, and the developmental trajectory of RI effects is unclear. Here we found that depotentiation in the hippocampal dentate gyrus (DG) depends on GluN2A-containing NMDA receptors (NMDARs). The susceptibility of LTP to disruption progressively increases with the rise in the GluN2A/GluN2B ratio during development.The vulnerability of hippocampus-dependent memory to interference from post-learning novelty exploration is subject to similar developmental regulation by NMDARs. Both GluN2A overexpression and GluN2B downregulation in the DG promote RIinduced forgetting. Altogether, our results suggest that a switch in GluN2 subunit predominance may confer age-related differences to depotentiation and underlie the developmental decline in memory resistance to RI.

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats

“…Artificially increasing the NR2A/NR2B ratio by lentivirus-mediated NR2A overexpression or downregulation of NR2B in the mouse hippocampus promoted depotentiation without producing apparent deleterious effects on LTP. As a result, animals could learn the fear conditioning task normally, whereas only memory retention was particularly impaired, indicating a key role of the NR2A subunit component in memory loss [95]. Assuming the correlation between depotentiation and memory loss, in the present work, TBS-induced LTP remained stable after blockade of the NR2B subunit, indicating no role in depotentiation for this sub-type NMDAR.…”

The role of GFAP and vimentin in learning and memory

“…Notably, mice with reduced neurogenesis may exhibit enhanced place and reversal learning due to higher synaptic density (Perez-Alcazar et al, 2014;Shi et al, 2015). In addition, memory and forgetting processes are regulated at the level of NMDAR composition (Ge et al, 2019).…”

Pre-plaque Aß-Mediated Impairment of Synaptic Depotentiation in a Transgenic Rat Model of Alzheimer’s Disease Amyloidosis

“…A corollary of the widely accepted theory that LTP-like persistent synaptic strengthening provides an essential component of memory formation is that depotentiation will promote memory erasure. Indeed, interventions, including novelty exploration, that relatively selectively induce depotentiation can trigger the erasure of newly formed memories or habits (Hayashi-Takagi et al, 2015; Medina, 2018; Ge et al, 2019). Investigating whether patients with early AD have a deficit in memory interference from novel information is a topic worth pursuing (Muecke et al, 2018; Thomas et al, 2018).…”