Thongrong Sitthisak, Hausott Barbara, Marvaldi Letizia, Agostinho Alexandra S, Zangrandi Luca, Burtscher Johannes, Fogli Barbara, Schwarzer Christoph, Klimaschewski Lars
Division of Neuroanatomy, Department of Anatomy Histology and Embryology, Medical University, Innsbruck, 6020, Innsbruck, Austria.
Department of Pharmacology, Medical University Innsbruck, Innsbruck, 6020, Austria.
Hippocampus. 2016 May;26(5):658-67. doi: 10.1002/hipo.22549. Epub 2015 Nov 27.
Sprouty (Spry) proteins play a key role as negative feedback inhibitors of the Ras/Raf/MAPK/ERK pathway downstream of various receptor tyrosine kinases. Among the four Sprouty isoforms, Spry2 and Spry4 are expressed in the hippocampus. In this study, possible effects of Spry2 and Spry4 hypomorphism on neurodegeneration and seizure thresholds in a mouse model of epileptogenesis was analyzed. The Spry2/4 hypomorphs exhibited stronger ERK activation which was limited to the CA3 pyramidal cell layer and to the hilar region. The seizure threshold of Spry2/4(+/-) mice was significantly reduced at naive state but no difference to wildtype mice was observed 1 month following KA treatment. Histomorphological analysis revealed that dentate granule cell dispersion (GCD) was diminished in Spry2/4(+/-) mice in the subchronic phase after KA injection. Neuronal degeneration was reduced in CA1 and CA3 principal neuron layers as well as in scattered neurons of the contralateral CA1 and hilar regions. Moreover, Spry2/4 reduction resulted in enhanced survival of somatostatin and neuropeptide Y expressing interneurons. GFAP staining intensity and number of reactive astrocytes markedly increased in lesioned areas of Spry2/4(+/-) mice as compared with wildtype mice. Taken together, although the seizure threshold is reduced in naive Spry2/4(+/-) mice, neurodegeneration and GCD is mitigated following KA induced hippocampal lesions, identifying Spry proteins as possible pharmacological targets in brain injuries resulting in neurodegeneration. The present data are consistent with the established functions of the ERK pathway in astrocyte proliferation as well as protection from neuronal cell death and suggest a novel role of Spry proteins in the migration of differentiated neurons.
Sprouty（Spry）蛋白作为各种受体酪氨酸激酶下游Ras/Raf/MAPK/ERK通路的负反馈抑制剂发挥关键作用。在四种Sprouty亚型中，Spry2和Spry4在海马体中表达。在本研究中，分析了Spry2和Spry4低表达对癫痫发生小鼠模型中神经退行性变和癫痫发作阈值的可能影响。Spry2/4低表达小鼠表现出更强的ERK激活，这种激活仅限于CA3锥体细胞层和门区。Spry2/4(+/-)小鼠在未处理状态下癫痫发作阈值显著降低，但在KA处理1个月后与野生型小鼠无差异。组织形态学分析显示，KA注射后亚慢性期Spry2/4(+/-)小鼠的齿状颗粒细胞分散（GCD）减少。CA1和CA3主要神经元层以及对侧CA1和门区的散在神经元中的神经元变性减少。此外，Spry2/4表达降低导致表达生长抑素和神经肽Y的中间神经元存活率提高。与野生型小鼠相比，Spry2/4(+/-)小鼠损伤区域的GFAP染色强度和反应性星形胶质细胞数量明显增加。综上所述，虽然未处理的Spry2/4(+/-)小鼠癫痫发作阈值降低，但KA诱导海马损伤后神经退行性变和GCD减轻，表明Spry蛋白可能是导致神经退行性变的脑损伤中的药理学靶点。目前的数据与ERK通路在星形胶质细胞增殖以及保护神经元细胞死亡方面的既定功能一致，并提示Spry蛋白在分化神经元迁移中的新作用。
