Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments
Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments
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DOI：
10.1007/s12035-014-8953-9
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发表时间：
2015-12-01
影响因子：
5.1
通讯作者：
Zhu, Ling-Qiang
中科院分区：
文献类型：
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作者：
Hu, Juan;Huang, He-Zhou;Zhu, Ling-Qiang
嗅觉障碍的人群显示出海马体依赖的情景记忆缺陷的机会增加。虽然已经知道嗅觉信息通过内嗅皮层第二层投射到海马区，但将嗅觉缺陷与海马区联系起来的分子机制尚不清楚。以双侧嗅球切开术(OBX)为模型，我们发现OBX通过激活海马提取液中的几种记忆相关蛋白激酶，包括糖原合成酶-3β(GSK-3β)、蛋白激酶A(PKA)、细胞外信号调节激酶(ERK)、c-jun氨基末端激酶(JNK)、磷脂酰肌醇-3-激酶(PI3K)和蛋白激酶B(PKB)而导致记忆障碍。OBX大鼠还表现出长时程增强(LTP)的抑制；突触素I、突触素、NR2A/B和PSD95的减少；突触前活动区和突触后密度变薄，突触空间扩大；脊椎数量和蘑菇型棘突减少；tau过度磷酸化。尾静脉注射SB216763数周后，选择性抑制GSK-3β可通过恢复突触成分和tau磷酸化来改善OBX所致的记忆障碍。此外，用携带慢病毒的shRNA对GSK-3β进行基因消融，有效地挽救了记忆缺陷、突触障碍和转位。我们的数据表明，GSK-3激活介导了海马区的嗅觉障碍，靶向GSK-3阻断了这种病理联系。
The populations with olfactory dysfunction show an increased chance for hippocampus-dependent episodic memory deficit. Although it is known that the olfactory information projects to the hippocampus through entorhinal cortex layer II, the molecular mechanisms linking olfactory deficit to the hippocampus is not understood. Using bilateral olfactory bulbectomy (OBX) as a model, we found that OBX induced memory deficits with activation of several memory-related protein kinases in the hippocampal extracts, including glycogen synthase kinase-3 beta (GSK-3 beta), protein kinase A (PKA), extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB). The OBX rats also show suppression of long-term potentiation (LTP); reduction of synapsin I, synaptophysin, NR2A/B, and PSD95; thinner presynaptic active zone and postsynaptic density with enlarged synaptic space; decreased spine numbers and mushroom-type spines; and tau hyperphosphorylation. After injection of SB216763 for several weeks by vena caudalis, selective inhibition of GSK-3 beta ameliorated the OBX-induced memory deficits with recovery of the synaptic components and tau phosphorylation. Furthermore, genetic ablation of GSK-3 beta by lentivirus-packed shRNA effectively rescued the memory deficits, synaptic disorder, and tauopathy. Our data indicate that GSK-3 activation mediates the olfactory deficits to the hippocampus, and targeting GSK-3 blocks the pathological connection.