Álvarez-Ferradas Carla, Wellmann Mario, Morales Koyam, Fuenzalida Marco, Cerpa Waldo, Inestrosa Nibaldo C, Bonansco Christian
Facultad de Ciencias, Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Universidad de Valparaíso, Valparaíso, Chile.
Escuela de Fonoaudiología, Facultad de Medicina, Universidad de Valparaíso, Valparaíso, Chile.
Front Mol Neurosci. 2022 Oct 28;15:1024034. doi: 10.3389/fnmol.2022.1024034. eCollection 2022.
Synapse unsilencing is an essential mechanism for experience-dependent plasticity. Here, we showed that the application of the ligand Wnt-5a converts glutamatergic silent synapses into functional ones by increasing both α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) currents (I and I, respectively). These effects were mimicked by the hexapeptide Foxy-5 and inhibited by secreted frizzled-related protein sFRP-2. I potentiation was produced by increased synaptic potency, followed by an increase in the probability of release (Pr), even in the presence of 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX). At a longer time of Wnt-5a exposure, the Pr increments were higher in I than in I. In the presence of NMDAR inhibitors, Wnt-5a-induced conversion was fully inhibited in 69.0% of silent synapses, whereas in the remaining synapses were converted into functional one. Our study findings showed that the Wnt-5a-activated pathway triggers AMPAR insertion into mammalian glutamatergic synapses, unsilencing non-functional synapses and promoting the formation of nascent synapses during the early postnatal development of the brain circuits.
突触去沉默是经验依赖性可塑性的一种重要机制。在这里，我们表明，应用配体Wnt-5a可通过增加α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）电流和N-甲基-D-天冬氨酸（NMDA）电流（分别为I和I），将谷氨酸能沉默突触转变为功能性突触。六肽Foxy-5可模拟这些效应，而分泌型卷曲相关蛋白sFRP-2则可抑制这些效应。即使在存在7-硝基-2,3-二氧代-1,4-二氢喹喔啉-6-腈（CNQX）的情况下，I增强也是由突触效能增加引起的，随后释放概率（Pr）增加。在较长时间暴露于Wnt-5a的情况下，I中的Pr增量高于I中的Pr增量。在存在NMDAR抑制剂的情况下，Wnt-5a诱导的转变在69.0%的沉默突触中被完全抑制，而其余突触则转变为功能性突触。我们的研究结果表明，Wnt-5a激活的途径触发AMPA受体插入哺乳动物谷氨酸能突触，使无功能突触去沉默，并在脑回路出生后早期发育过程中促进新生突触的形成。
