ArticleBiological psychiatry2023
NMDA Receptor-Arc Signaling Is Required for Memory Updating and Is Disrupted in Alzheimer's Disease.
Article in Biological psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
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- The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer's disease.Archives of toxicology · 2025Review
- Genetic Mechanisms of Experience-Dependent Neuronal Plasticity.Annual review of genetics · 2025Review
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- Article
- NMDA Receptors Coordinate Metabolic Reprogramming and Mitophagy in Schwann Cells to Promote Peripheral Nerve Regeneration.Research (Washington, D.C.) · 2025Article
- Combination of Haloperidol With UNC9994, β-arrestin-Biased Analog of Aripiprazole, Ameliorates Schizophrenia-Related Phenotypes Induced by NMDAR Deficit in Mice.The international journal of neuropsychopharmacology · 2024Article
- Transcriptome analysis of the aged SAMP8 mouse model of Alzheimer's disease reveals novel molecular targets of formononetin protection.Frontiers in pharmacology · 2024Article
Corrections and comments
- Commented on by
- Erratum issuedErratum.2023
Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMemory 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.
methodsWe describe a novel transduction pathway that links the NMDA receptor (NMDAR) to AKT signaling via the immediate early gene Arc and evaluate its role in memory. The signaling pathway is validated using biochemical tools and transgenic mice, and function is evaluated in assays of synaptic plasticity and behavior. The translational relevance is evaluated in human postmortem brain.
resultsArc is dynamically phosphorylated by CaMKII (calcium/calmodulin-dependent protein kinase II) and binds the NMDAR subunits NR2A/NR2B and a previously unstudied PI3K (phosphoinositide 3-kinase) adapter p55PIK (PIK3R3) in vivo in response to novelty or tetanic stimulation in acute slices. NMDAR-Arc-p55PIK recruits p110α PI3K and mTORC2 (mechanistic target of rapamycin complex 2) to activate AKT. NMDAR-Arc-p55PIK-PI3K-mTORC2-AKT assembly occurs within minutes of exploratory behavior and localizes to sparse synapses throughout hippocampal 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 conditional knockout 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.
conclusionsA 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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