Role of the Perisynaptic Extracellular Matrix in Synaptic Plasticity

周围神经网络(PNN)是成人脑细胞外基质的专门化。它们富含分泌的糖蛋白，如Tenascin-R，以及蛋白多糖，如Brivican或Neurcan。虽然PNN是围绕着大的神经元胞体和轴突形成的，但它们的大部分成分来自神经胶质细胞。在功能上，这些网状结构是在屏障形成的背景下讨论的，但最近的数据表明，PNN成分在突触可塑性中起着积极的作用。因此，我们建议(1)以分离的原代培养物中兴奋性突触和抑制性突触的形成为模型系统，研究PNN出现的条件。此外，(2)我们想要寻找短蛋白的(突触周围)结合伙伴，它可能作为突触周围的PNN锚定点。(3)研究基质金属蛋白酶对短蛋白的切割在突触可塑性中的作用。此外，(4)，我们建议对缺乏蛋白多糖和/或神经多糖的小鼠品系进行详细的表型研究，以了解受影响大脑的可塑性变化。我们的小鼠实验将包括对海马体结构的解剖学研究，对突触蛋白组分组成的生化分析，体外LTP测量，脑电记录和详细的行为测试，以阐明含有蛋白多糖的PNN对成年神经元可塑性的贡献。

Perineuronal nets (PNN) are specializations of the adult brain extracellular matrix. They are rich in secreted glycoproteins, like Tenascin-R, and proteoglycans, like brevican or neurocan. Although PNN are formed around large neuronal somata and neurites, a major fraction of their constituents derive from glial cells. Functionally these net-like structures are discussed in the context of barrier-formation, but recent data point to an active role of PNN components in synaptic plasticity. We therefore propose (1) to investigate the conditions for PNN emergence in relation to the formation of excitatory and inhibitory synapses in dissociated primary cultures as a model system. Furthermore, (2) we want to search for (peri-) synaptic binding partners for brevican, which might act as PNN-anchoring points around synaptic contacts and (3) investigate the role of brevican cleavage by matrix metalloproteases for synaptic plasticity. Moreover (4), we propose a detailed phenotypical investigation of mouse lines deficient for brevican, neurocan or both proteoglycans with respect to changes in the plastic properties of the affected brains. Our mouse experiments will include anatomical studies of the hippocampus architecture, biochemical analysis of the composition of synaptic protein fractions, in vitro LTP measurements, EEG recordings and a detailed behavioral testing to elucidate the contribution of proteoglycan-containing PNN to adult neuronal plasticity.