Hu Juan, Huang He-Zhou, Wang Xiang, Xie Ao-Ji, Wang Xiong, Liu Dan, Wang Jian-Zhi, Zhu Ling-Qiang
Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Oncology, The First College of Clinical Medical Science, China Three Gorges University and Yichang Central People's Hospital, No. 183 Yiling Road, Yichang, Hubei, 443003, China.
Mol Neurobiol. 2015 Dec;52(3):1601-1617. doi: 10.1007/s12035-014-8953-9. Epub 2014 Nov 5.
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-3β (GSK-3β), 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-3β ameliorated the OBX-induced memory deficits with recovery of the synaptic components and tau phosphorylation. Furthermore, genetic ablation of GSK-3β 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.
嗅觉功能障碍人群出现海马体依赖性情景记忆缺陷的几率增加。尽管已知嗅觉信息通过内嗅皮层第二层投射至海马体，但嗅觉缺陷与海马体之间的分子机制尚不清楚。我们以双侧嗅球切除（OBX）为模型，发现OBX诱导记忆缺陷，并激活海马体提取物中的几种记忆相关蛋白激酶，包括糖原合酶激酶-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）。OBX大鼠还表现出长时程增强（LTP）受抑制；突触素I、突触囊泡蛋白、NR2A/B和突触后致密蛋白95减少；突触前活性区变薄，突触后致密物减少，突触间隙增大；棘突数量减少，蘑菇型棘突减少；以及tau蛋白过度磷酸化。通过尾静脉注射SB216763数周后，对GSK-3β的选择性抑制改善了OBX诱导的记忆缺陷，同时突触成分和tau蛋白磷酸化得以恢复。此外，通过慢病毒包装的短发夹RNA对GSK-3β进行基因敲除有效地挽救了记忆缺陷、突触紊乱和tau蛋白病。我们的数据表明，GSK-3的激活介导了从嗅觉缺陷到海马体的过程，靶向GSK-3可阻断这种病理联系。
