Lauri S E, Kaukinen S, Kinnunen T, Ylinen A, Imai S, Kaila K, Taira T, Rauvala H
Department of Biosciences, Division of Animal Physiology, 00014 University of Helsinki, Helsinki, Finland.
J Neurosci. 1999 Feb 15;19(4):1226-35. doi: 10.1523/JNEUROSCI.19-04-01226.1999.
The cellular mechanisms responsible for synaptic plasticity involve interactions between neurons and the extracellular matrix. Heparan sulfates (HSs) constitute a group of glycosaminoglycans that accumulate in the beta-amyloid deposits in Alzheimer's disease and influence the development of neuron-target contacts by interacting with other cell surface and matrix molecules. However, the contribution of HSs to brain function is unknown. We found that HSs play a crucial role in long-term potentiation (LTP), a finding that is consistent with the idea that converging molecular mechanisms are used in the development of neuron-target contacts and in activity-induced synaptic plasticity in adults. Enzymatic cleavage of HS by heparitinase as well as addition of soluble heparin-type carbohydrates prevented expression of LTP in response to 100 Hz/1 sec stimulation of Schaffer collaterals in rat hippocampal slices. A prominent carrier protein for the type of glycans implicated in LTP regulation in the adult hippocampus was identified as N-syndecan (syndecan-3), a transmembrane proteoglycan that was expressed at the processes of the CA1 pyramidal neurons in an activity-dependent manner. Addition of soluble N-syndecan into the CA1 dendritic area prevented tetanus-induced LTP. A major substrate of src-type kinases, cortactin (p80/85), and the tyrosine kinase fyn copurified with N-syndecan from hippocampus. Moreover, association of both cortactin and fyn to N-syndecan was rapidly increased after induction of LTP. N-syndecan may thus act as an important regulator in the activity-dependent modulation of neuronal connectivity by transmitting signals between extracellular heparin-binding factors and the fyn signaling pathway.
负责突触可塑性的细胞机制涉及神经元与细胞外基质之间的相互作用。硫酸乙酰肝素（HSs）是一组糖胺聚糖，它们在阿尔茨海默病的β-淀粉样蛋白沉积物中积累，并通过与其他细胞表面和基质分子相互作用来影响神经元-靶标接触的发育。然而，HSs对脑功能的贡献尚不清楚。我们发现HSs在长时程增强（LTP）中起关键作用，这一发现与以下观点一致，即在神经元-靶标接触的发育以及成体中活动诱导的突触可塑性过程中使用了趋同的分子机制。用硫酸乙酰肝素酶对HS进行酶切以及添加可溶性肝素类碳水化合物可阻止大鼠海马切片中施万细胞侧支100Hz/1秒刺激所引发的LTP的表达。在成年海马体中，一种与LTP调节相关的聚糖类型的主要载体蛋白被鉴定为N-聚糖蛋白（聚糖蛋白-3），它是一种跨膜蛋白聚糖，以活动依赖的方式在CA1锥体神经元的突起处表达。向CA1树突区域添加可溶性N-聚糖蛋白可阻止强直刺激诱导的LTP。src型激酶的主要底物、皮层肌动蛋白（p80/85）以及酪氨酸激酶fyn与N-聚糖蛋白从海马体中共同纯化出来。此外，在诱导LTP后，皮层肌动蛋白和fyn与N-聚糖蛋白的结合迅速增加。因此，N-聚糖蛋白可能通过在细胞外肝素结合因子和fyn信号通路之间传递信号，在活动依赖的神经元连接调制中充当重要调节因子。
