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NMDA Receptor-Arc Signaling Is Required for Memory Updating and Is Disrupted in Alzheimer's Disease.
- Source :
-
Biological psychiatry [Biol Psychiatry] 2023 Nov 01; Vol. 94 (9), pp. 706-720. Date of Electronic Publication: 2023 Feb 14. - Publication Year :
- 2023
-
Abstract
- Background: 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.<br />Methods: We 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.<br />Results: Arc 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.<br />Conclusions: 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.<br /> (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Mice
Humans
Animals
Receptors, N-Methyl-D-Aspartate metabolism
N-Methylaspartate metabolism
Phosphatidylinositol 3-Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Glycogen Synthase Kinase 3 metabolism
Signal Transduction
Hippocampus metabolism
Mice, Transgenic
Mice, Knockout
Mechanistic Target of Rapamycin Complex 2 metabolism
Alzheimer Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2402
- Volume :
- 94
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Biological psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 36796600
- Full Text :
- https://doi.org/10.1016/j.biopsych.2023.02.008