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.
Methods
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.
Results
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.
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.
Key words
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Article info
Publication history
Accepted:
February 6,
2023
Received in revised form:
January 31,
2023
Received:
August 31,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Author contributions
L.Y., A.V.S. and P.F.W. designed the experiments. L.Y. performed most of the biochemical experiments. W.L. performed electrophysiology experiments. L.S. performed mouse behavioral experiments. J.W. investigated detailed Arc-p55PIK interaction and generated p55PIK cKO mouse. W.Z. identified Arc binding motifs in NMDA receptor. Y.C. generated rabbit polyclonal anti-p55PIK antibody and ArcP217F knock-in mouse. J.R. prepared human AD and control brain samples. A.K. supervised electrophysiology experiments. A.V.S. supervised mouse behavioral experiments. L.Y., A.V.S. and P.F.W prepared the manuscript.
Declaration of interests
The authors report no biomedical financial interests or potential conflicts of interest.
Identification
Copyright
© 2023 Society of Biological Psychiatry.
