RESUMEN
Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca2+ 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 Ca2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca2+-dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca2+-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-ß (Aß) may impair learning and memory through biasing NMDAR Ca2+ 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 Aß-mediated impairment of NMDAR synaptic Ca2+ influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aß 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 Ca2+ 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 Aß-mediated synaptic dysfunction.Significance Statement Understanding mechanisms of synaptic dysfunction in Alzheimer's disease (AD) is pivotal for therapeutic advances. Amyloid-ß oligomers (Aßo), primary culprits in AD pathology, disrupt critical synaptic plasticity mechanisms, leading to enhanced LTD and synaptic loss. However, the underlying signaling pathways remain elusive. Calcineurin (CaN), localized by AKAP79/150 at synapses, plays a key role in LTD formation. Inhibition of CaN mitigates Aßo-induced synaptic deficits, implicating its involvement in AD pathology. Our study shows that AKAP-anchored CaN is critical in acute Aßo-mediated inhibition of NMDAR Ca2+ signaling and dendritic spine loss. Additionally, we identify mGluR1 as an upstream regulator of these Aßo-induced deficits, highlighting several potential therapeutic targets for AD-related synaptic pathology.