Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612.
J Neurosci. 2023 Dec 6;43(49):8317-8335. doi: 10.1523/JNEUROSCI.1113-23.2023.
Protein palmitoylation is the only reversible post-translational lipid modification. Palmitoylation is held in delicate balance by depalmitoylation to precisely regulate protein turnover. While over 20 palmitoylation enzymes are known, depalmitoylation is conducted by fewer enzymes. Of particular interest is the lack of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) that causes the devastating pediatric neurodegenerative condition infantile neuronal ceroid lipofuscinosis (CLN1). While most of the research on Ppt1 function has centered on its role in the lysosome, recent findings demonstrated that many Ppt1 substrates are synaptic proteins, including the AMPA receptor (AMPAR) subunit GluA1. Still, the impact of Ppt1-mediated depalmitoylation on synaptic transmission and plasticity remains elusive. Thus, the goal of the present study was to use the mouse model (both sexes) to determine whether Ppt1 regulates AMPAR-mediated synaptic transmission and plasticity, which are crucial for the maintenance of homeostatic adaptations in cortical circuits. Here, we found that basal excitatory transmission in the visual cortex is developmentally regulated and that chemogenetic silencing of the visual cortex excessively enhanced the synaptic expression of GluA1. Furthermore, triggering homeostatic plasticity in primary neurons caused an exaggerated incorporation of GluA1-containing, calcium-permeable AMPARs, which correlated with increased GluA1 palmitoylation. Finally, Ca imaging in awake mice showed visual cortical neurons favor a state of synchronous firing. Collectively, our results elucidate a crucial role for Ppt1 in AMPAR trafficking and show that impeded proteostasis of palmitoylated synaptic proteins drives maladaptive homeostatic plasticity and abnormal recruitment of cortical activity in CLN1. Neuronal communication is orchestrated by the movement of receptors to and from the synaptic membrane. Protein palmitoylation is the only reversible post-translational lipid modification, a process that must be balanced precisely by depalmitoylation. The significance of depalmitoylation is evidenced by the discovery that mutation of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (Ppt1) causes severe pediatric neurodegeneration. In this study, we found that the equilibrium provided by Ppt1-mediated depalmitoylation is critical for AMPA receptor (AMPAR)-mediated plasticity and associated homeostatic adaptations of synaptic transmission in cortical circuits. This finding complements the recent explosion of palmitoylation research by emphasizing the necessity of balanced depalmitoylation.
蛋白质棕榈酰化是唯一的可逆转的翻译后脂质修饰。棕榈酰化通过去棕榈酰化来精确调控蛋白质周转，处于微妙的平衡中。尽管已知有 20 多种棕榈酰化酶，但去棕榈酰化酶的数量较少。特别引人关注的是，缺乏去棕榈酰化酶棕榈酰蛋白硫酯酶 1（PPT1）会导致毁灭性的儿科神经退行性疾病婴儿神经元蜡样脂褐质沉积症（CLN1）。虽然关于 Ppt1 功能的大多数研究都集中在其在溶酶体中的作用，但最近的发现表明，许多 Ppt1 底物是突触蛋白，包括 AMPA 受体（AMPAR）亚基 GluA1。尽管如此，PPT1 介导的去棕榈酰化对突触传递和可塑性的影响仍然难以捉摸。因此，本研究的目的是使用 小鼠模型（雌雄两性）来确定 Ppt1 是否调节 AMPAR 介导的突触传递和可塑性，这对于皮质回路中维持稳态适应至关重要。在这里，我们发现 视觉皮层中的基础兴奋性传递受到发育调控，化学遗传学沉默 视觉皮层会过度增强 GluA1 的突触表达。此外，在原代神经元中触发稳态可塑性会导致包含 GluA1 的、钙通透性 AMPAR 的过度掺入，这与 GluA1 棕榈酰化增加相关。最后，在清醒的 小鼠的钙成像显示，视觉皮层神经元倾向于同步发射。总的来说，我们的结果阐明了 Ppt1 在 AMPAR 运输中的关键作用，并表明棕榈酰化突触蛋白的蛋白质稳态受到阻碍会导致 CLN1 中的适应不良的稳态可塑性和皮质活动的异常募集。神经元通讯是通过受体在突触膜之间的运动来协调的。蛋白质棕榈酰化是唯一的可逆转的翻译后脂质修饰，这一过程必须通过去棕榈酰化来精确平衡。去棕榈酰化的重要性体现在发现去棕榈酰化酶棕榈酰蛋白硫酯酶 1（Ppt1）的突变会导致严重的儿科神经退行性变。在这项研究中，我们发现 Ppt1 介导的去棕榈酰化提供的平衡对于 AMPA 受体（AMPAR）介导的可塑性以及皮质回路中突触传递的相关稳态适应至关重要。这一发现补充了最近的棕榈酰化研究爆炸，强调了平衡去棕榈酰化的必要性。
