Behind the scenes: Are latent memories supported by calcium independent plasticity?

Abstract

N‐methyl‐D‐aspartate receptors (NMDARs) can be considered to be the de facto “plasticity” receptors in the brain due to their central role in the activity‐dependent modification of neuronal morphology and synaptic transmission. Since the 1980s, research on NMDARs has focused on the second messenger properties of calcium and the downstream signaling pathways that mediate alterations in neural form and function. Recently, NMDARs were shown to drive activity‐dependent synaptic plasticity without calcium influx. How this “nonionotropic” plasticity occurs in vitro is becoming clearer, but research on its involvement in behavior and cognition is in its infancy. There is a partial overlap in the downstream signaling molecules that are involved in ionotropic and nonionotropic NMDAR‐dependent plasticity. Given this, and prior studies of the cognitive impacts of ionotropic NMDAR plasticity, a preliminary model explaining how NMDAR nonionotropic plasticity affects learning and memory can be established. We hypothesize that nonionotropic NMDAR plasticity takes part in latent memory encoding in immature rodents through nonassociative depression of synaptic efficacy, and possibly shrinking of dendritic spines. Further, the late postnatal alteration in NMDAR composition in the hippocampus appears to reduce nonionotropic signaling and remove a restriction on memory retrieval. This framework substantially alters the canonical model of NMDAR involvement in spatial cognition and hippocampal maturation and provides novel and exciting inroads for future studies.

Individual NMDA receptor GluN2 subunit signaling domains differentially regulate the postnatal maturation of hippocampal excitatory synaptic transmission and plasticity but not dendritic morphology

“…Conversely, the GluN2A CTD is selectively phosphorylated by protein kinase A (PKA) (Wang et al., 2014) and interacts more with Ras–Grf2 and extracellular‐regulated kinase (ERK) (Jin & Feig, 2010). Thus, while numerous molecular partners for GluN2B and GluN2A subunits are well characterized (Keith et al., 2022), how separate GluN2B‐ and GluN2A‐mediated signaling streams direct physiological and morphological development is not fully understood.…”