Amyloid-β Causes NMDA Receptor Dysfunction and Dendritic Spine Loss through mGluR1 and AKAP150-Anchored Calcineurin Signaling

• Published in: The Journal of neuroscience Vol. 44; no. 37
• Main Authors: Prikhodko, Olga, Freund, Ronald K, Sullivan, Emily, Kennedy, Matthew J, Dell'Acqua, Mark L
• Format: Journal Article
• Language: English
• Published: United States 11-09-2024
• Subjects: A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; Amyloid beta-Peptides - metabolism; Animals; Calcineurin - metabolism; Dendritic Spines - metabolism; Female; Hippocampus - metabolism; Hippocampus - pathology; Long-Term Synaptic Depression - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Signal Transduction - physiology; amyloid-β; mGluR1; dendritic spine; NMDA receptor; calcineurin; AKAP
• ISSN: 1529-2401
• DOI: 10.1523/JNEUROSCI.0675-24.2024

Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca
influx through postsynaptic NMDA-type glutamate receptors (NMDARs) initiates signaling pathways that coordinate changes in dendritic spine structure and synaptic function. During long-term potentiation (LTP), high levels of NMDAR Ca
influx promote increases in both synaptic strength and dendritic spine size through activation of Ca
-dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca
influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca
-dependent protein phosphatase calcineurin (CaN), which is anchored at synapses via the scaffold protein A-kinase anchoring protein (AKAP)150. In Alzheimer's disease (AD), the pathological agent amyloid-β (Aβ) may impair learning and memory through biasing NMDAR Ca
signaling pathways toward LTD and spine elimination. By employing AKAP150 knock-in mice of both sexes with a mutation that disrupts CaN anchoring to AKAP150, we revealed that local, postsynaptic AKAP-CaN-LTD signaling was required for Aβ-mediated impairment of NMDAR synaptic Ca
influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aβ acutely engages AKAP-CaN signaling through activation of G-protein-coupled metabotropic glutamate receptor 1 (mGluR1) leading to dephosphorylation of NMDAR GluN2B subunits, which decreases Ca
influx to favor LTD over LTP, and cofilin, which promotes F-actin severing to destabilize dendritic spines. These findings reveal a novel interplay between NMDAR and mGluR1 signaling that converges on AKAP-anchored CaN to coordinate dephosphorylation of postsynaptic substrates linked to multiple aspects of Aβ-mediated synaptic dysfunction.