A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to Postsynaptic mTORC1
A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to Postsynaptic mTORC1
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DOI：
10.1523/jneurosci.1789-17.2018
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发表时间：
2018-02-28
影响因子：
5.3
通讯作者：
Sutton, Michael A.
中科院分区：
文献类型：
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作者：
Henry, Fredrick E.;Wang, Xiao;Sutton, Michael A.
mTORC 1依赖的翻译控制在突触可塑性的几种持久形式中起关键作用，例如长时程增强（LTP）和mGluR依赖的长时程抑制。最近的证据表明，一个额外的作用，在调节突触稳态响应于不活动，树突mTORC 1通过逆行信号调节突触前功能。目前，尚不清楚LTP和稳态可塑性是否使用mTORC 1依赖性信号传导的共同途径，或者是否各自通过不同的途径参与mTORC 1。在这里，我们报告了一个独特的信号通路，专门耦合稳态信号突触后mTORC 1兴奋性突触输入丢失后。我们发现，AMPAR的封锁，而不是LTP诱导的刺激，诱导磷脂酶D（PLD）依赖性合成的脂质第二信使磷脂酸（PA）在培养的大鼠海马神经元的性别。PLD 1/2的药理学阻断或PA与mTOR相互作用的药物遗传学破坏消除了mTORC 1信号传导和由AMPAR阻断驱动的突触前补偿，但不会改变mTORC 1激活或化学LTP（cLTP）期间的功能变化。过表达的PLD 1，但不是PLD 2，重演功能性突触的变化，以及与稳态可塑性相关的签名细胞适应。最后，外源性PA的瞬时应用足以驱动快速突触前补偿，需要mTORC 1依赖的BDNF在突触后室的翻译。因此，这些结果定义了一个独特的稳态信号通路耦合mTORC 1激活兴奋性突触驱动的变化。我们的研究结果进一步表明，一个以上的典型mTORC 1激活途径可能是相关的设计新的治疗方法对神经发育障碍与mTORC 1失调。
mTORC1-dependent translational control plays a key role in several enduring forms of synaptic plasticity such as long term potentiation (LTP) and mGluR-dependent long term depression. Recent evidence demonstrates an additional role in regulating synaptic homeostasis in response to inactivity, where dendritic mTORC1 serves to modulate presynaptic function via retrograde signaling. Presently, it is unclear whether LTP and homeostatic plasticity use a common route to mTORC1-dependent signaling or whether each engage mTORC1 through distinct pathways. Here, we report a unique signaling pathway that specifically couples homeostatic signaling to postsynaptic mTORC1 after loss of excitatory synaptic input. We find that AMPAR blockade, but not LTP-inducing stimulation, induces phospholipase D (PLD)-dependent synthesis of the lipid second messenger phosphatidic acid (PA) in rat cultured hippocampal neurons of either sex. Pharmacological blockade of PLD1/2 or pharmacogenetic disruption of PA interactions with mTOR eliminates mTORC1 signaling and presynaptic compensation driven by AMPAR blockade, but does not alter mTORC1 activation or functional changes during chemical LTP (cLTP). Overexpression of PLD1, but not PLD2, recapitulates both functional synaptic changes as well as signature cellular adaptations associated with homeostatic plasticity. Finally, transient application of exogenous PA is sufficient to drive rapid presynaptic compensation requiring mTORC1-dependent translation of BDNF in the postsynaptic compartment. These results thus define a unique homeostatic signaling pathway coupling mTORC1 activation to changes in excitatory synaptic drive. Our results further imply that more than one canonical mTORC1 activation pathway may be relevant for the design of novel therapeutic approaches against neurodevelopmental disorders associated with mTORC1 dysregulation.