Phospholipase C is required for changes in postsynaptic structure and function associated with NMDA receptor-dependent long-term depression
Phospholipase C is required for changes in postsynaptic structure and function associated with NMDA receptor-dependent long-term depression
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DOI：
10.1523/jneurosci.4340-06.2007
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发表时间：
2007-03-28
影响因子：
5.3
通讯作者：
Dell'Acqua, Mark L.
中科院分区：
文献类型：
--
作者：
Horne, Eric A.;Dell'Acqua, Mark L.
NMDA受体（NMDAR）依赖的海马突触可塑性是学习和记忆的基础，通过知之甚少的机制协调调节树突棘结构和AMPA受体（AMPAR）突触后强度。长期抑制（LTD）的诱导激活蛋白磷酸酶2B/钙调神经磷酸酶（CaN），导致树突棘收缩通过肌动蛋白解聚和AMPAR抑制通过受体去磷酸化和内化。支架蛋白A-激酶锚定蛋白79/150（AKAP 79/150）和突触后密度95（PSD 95）形成复合物，其控制cAMP依赖性蛋白激酶（PKA）和CaN在AMPAR磷酸化调节中的相反作用。在LTD过程中，海马神经元中的AKAP 79/150-PSD 95复合物被破坏，与AMPAR的内化一致，PSD 95水平降低，以及AKAP 79/150和PKA从棘中丢失。AKAP 79/150通过结合F-肌动蛋白和磷脂酰肌醇-（4，5）二磷酸（PIP 2）靶向刺。以前的电生理学研究表明，抑制磷脂酶C（PLC）催化的水解PIP 2抑制NMDAR依赖性LTD;然而，连接PLC激活的树突棘结构和LTD中AMPAR功能的改变的信号转导机制是未知的。我们在这里表明，NMDAR刺激PLC在培养的海马神经元是必要的AKAP 79/150的损失从棘和解聚的棘肌动蛋白。重要的是，我们证明了PLC的NMDAR激活对于脊柱PSD 95水平和AMPAR内化的降低也是必要的。因此，PLC信号传导是LTD突触后表达所需的脊柱肌动蛋白、PSD支架和AMPAR运输的结构和功能变化所必需的。
NMDA receptor (NMDAR)-dependent hippocampal synaptic plasticity underlying learning and memory coordinately regulates dendritic spine structure and AMPA receptor (AMPAR) postsynaptic strength through poorly understood mechanisms. Induction of longterm depression (LTD) activates protein phosphatase 2B/calcineurin (CaN), leading to dendritic spine shrinkage through actin depolymerization and AMPAR depression through receptor dephosphorylation and internalization. The scaffold proteins A-kinase-anchoring protein 79/150 (AKAP79/150) and postsynaptic density 95 (PSD95) form a complex that controls the opposing actions of the cAMP-dependent protein kinase (PKA) and CaN in regulation of AMPAR phosphorylation. The AKAP79/150-PSD95 complex is disrupted in hippocampal neurons during LTD coincident with internalization of AMPARs, decreases in PSD95 levels, and loss of AKAP79/150 and PKA from spines. AKAP79/150 is targeted to spines through binding F-actin and the phospholipid phosphatidylinositol-(4,5)bisphosphate (PIP2). Previous electrophysiological studies have demonstrated that inhibition of phospholipase C (PLC)-catalyzed hydrolysis of PIP2 inhibits NMDAR-dependent LTD; however, the signaling mechanisms that link PLC activation to alterations in dendritic spine structure and AMPAR function in LTD are unknown. We show here that NMDAR stimulation of PLC in cultured hippocampal neurons is necessary for AKAP79/150 loss from spines and depolymerization of spine actin. Importantly, we demonstrate that NMDAR activation of PLC is also necessary for decreases in spine PSD95 levels and AMPAR internalization. Thus, PLC signaling is required for structural and functional changes in spine actin, PSD scaffolding, and AMPAR trafficking underlying postsynaptic expression of LTD.