Archival Report|Articles in Press

NMDAR-Arc signaling is required for Memory Updating and is disrupted in Alzheimer’s Disease

Published:February 14, 2023DOI:



      Memory deficits are central to many neuropsychiatric diseases. During acquisition of new information memories can become vulnerable to interference, yet mechanisms that underlie interference are unknown.


      We describe a novel transduction pathway that links NMDAR to AKT signaling via the IEG Arc, and evaluate its role in memory. The signaling pathway is validated using biochemical tools and genetic animals, and function is evaluated in assays of synaptic plasticity and behavior. The translational relevance is evaluated in human postmortem brain.


      Arc is dynamically phosphorylated by CaMKII and binds the NMDA receptor (NMDAR) subunits NR2A/NR2B and a previously unstudied PI3K adaptor p55PIK (PIK3R3) in vivo in response to novelty or tetanic stimulation in acute slices. NMDAR-Arc-p55PIK recruits p110α PI3K and mTORC2 to activate AKT. NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT assembly occurs within minutes of exploratory behavior and localizes to sparse synapses throughout hippocampus and cortical regions. Studies using conditional (Nestin-Cre) p55PIK deletion mice indicate that NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT functions to inhibit GSK3 and mediates input-specific metaplasticity that protects potentiated synapses from subsequent depotentiation. p55PIK cKO mice perform normally in multiple behaviors including working-memory and long-term memory tasks but exhibit deficits indicative of increased vulnerability to interference in both short-term and long-term paradigms. The NMDAR-AKT transduction complex is reduced in postmortem brain of individuals with early Alzheimer’s disease.


      A novel function of Arc mediates synapse-specific NMDAR-AKT signaling and metaplasticity that contributes to memory updating and is disrupted in human cognitive disease.

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