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; p. e0675242024
• Main Authors: Prikhodko, Olga, Freund, Ronald K, Sullivan, Emily, Kennedy, Matthew J, Dell'Acqua, Mark L
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 11.09.2024
• Subjects: A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; A kinase-anchoring protein; Actin; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Calcineurin; Calcineurin - metabolism; Calcium influx; Calcium ions; Calcium signalling; Cofilin; Dendritic plasticity; Dendritic spines; Dendritic Spines - metabolism; Dendritic structure; Dephosphorylation; Female; Glutamate receptors; Glutamic acid receptors (ionotropic); Glutamic acid receptors (metabotropic); Hippocampus - metabolism; Hippocampus - pathology; Kinases; Learning; Long-term depression; Long-term potentiation; Long-Term Synaptic Depression - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; N-Methyl-D-aspartic acid receptors; Neurodegenerative diseases; Protein A; Proteins; Receptor mechanisms; Receptors; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Signal transduction; Signal Transduction - physiology; Structure-function relationships; Substrates; Synapses; Synaptic depression; Synaptic plasticity; Synaptic strength; β-Amyloid; amyloid-β; mGluR1; dendritic spine; NMDA receptor; calcineurin; AKAP
• ISSN: 0270-6474; 1529-2401; 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.