Institute of Neuroscience, National Research Council CNR, Via Moruzzi, 1, 56124, Pisa, Italy.
Laboratory for Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Science, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands.
Mol Neurobiol. 2019 Sep;56(9):5987-5997. doi: 10.1007/s12035-019-1499-0. Epub 2019 Jan 31.
Perineuronal nets (PNNs) are condensed structures in the extracellular matrix that mainly surround GABA-ergic parvalbumin-positive interneurons in the adult brain. Previous studies revealed a parallel between PNN formation and the closure of the critical period. Moreover, ocular dominance plasticity is enhanced in response to PNN manipulations in adult animals. However, the mechanisms through which perineuronal nets modulate plasticity are still poorly understood. Recent work indicated that perineuronal nets may convey molecular signals by binding and storing proteins with important roles in cellular communication. Here we report that semaphorin3A (Sema3A), a chemorepulsive axon guidance cue known to bind to important perineuronal net components, is necessary to dampen ocular dominance plasticity in adult rats. First, we showed that the accumulation of Sema3A in PNNs in the visual cortex correlates with critical period closure, following the same time course of perineuronal nets maturation. Second, the accumulation of Sema3A in perineuronal nets was significantly reduced by rearing animals in the dark in the absence of any visual experience. Finally, we developed and characterized a tool to interfere with Sema3A signaling by means of AAV-mediated expression of receptor bodies, soluble proteins formed by the extracellular domain of the endogenous Sema3A receptor (neuropilin1) fused to a human IgG Fc fragment. By using this tool to antagonize Sema3A signaling in the adult rat visual cortex, we found that the specific inhibition of Sema3A promoted ocular dominance plasticity. Thus, Sema3A accumulates in perineuronal nets in an experience-dependent manner and its presence in the mature visual cortex inhibits plasticity.
周围神经毡（PNNs）是细胞外基质中的浓缩结构，主要围绕 GABA 能的 Parvalbumin 阳性中间神经元。先前的研究表明，PNN 的形成与关键期的关闭之间存在平行关系。此外，在成年动物中，PNN 的操作会增强眼优势可塑性。然而，PNN 如何调节可塑性的机制仍知之甚少。最近的研究表明，PNN 可能通过结合和储存具有细胞通讯重要作用的蛋白质来传递分子信号。在这里，我们报告说，神经调节蛋白 3A（Sema3A），一种已知与重要的 PNN 成分结合的趋化性轴突导向信号，对于抑制成年大鼠的眼优势可塑性是必需的。首先，我们表明，Sema3A 在视觉皮层中的 PNN 中的积累与关键期的关闭相关，与 PNN 成熟的时间过程相同。其次，在没有任何视觉经验的黑暗中饲养动物，会显著减少 PNN 中 Sema3A 的积累。最后，我们开发并表征了一种通过 AAV 介导的受体体表达来干扰 Sema3A 信号的工具，受体体是由内源性 Sema3A 受体（神经调节蛋白 1）的细胞外结构域融合到人 IgG Fc 片段形成的可溶性蛋白。通过使用该工具在成年大鼠视觉皮层中拮抗 Sema3A 信号，我们发现 Sema3A 的特异性抑制促进了眼优势可塑性。因此，Sema3A 以经验依赖的方式在 PNN 中积累，其在成熟的视觉皮层中的存在抑制了可塑性。
