树突棘
钙调神经磷酸酶
NMDA受体
代谢型谷氨酸受体1
神经科学
脊柱(分子生物学)
细胞生物学
受体
医学
生物
内科学
代谢型谷氨酸受体
海马结构
移植
作者
Olga Prikhodko,Ronald K. Freund,Emily Sullivan,Matthew J. Kennedy,Mark L. Dell’Acqua
标识
DOI:10.1523/jneurosci.0675-24.2024
摘要
Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca 2+ 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 2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca 2+ -dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca 2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca 2+ -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 2+ 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 2+ 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 2+ 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI