Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity.
Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity.
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DOI：
10.1371/journal.pone.0031124
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pedarzani P
中科院分区：
文献类型：
--
作者：
Costello DA;Claret M;Al-Qassab H;Plattner F;Irvine EE;Choudhury AI;Giese KP;Withers DJ;Pedarzani P
糖尿病与认知缺陷和痴呆风险增加有关，尤其是在老年人中。这些缺陷和相应的神经生理结构和功能改变与代谢和血管变化有关，与慢性高血糖有关，但也可能与大脑中胰岛素作用的缺陷有关。为了阐明脑胰岛素信号在与认知过程相关的神经元功能中的具体作用，我们研究了缺乏胰岛素受体底物蛋白2 （IRS-2）的小鼠海马中神经元的行为和突触可塑性。为了在没有高血糖等混杂因素的情况下研究神经元功能和突触可塑性，我们使用了中枢神经系统（CNS）限制性缺失IRS-2 （NesCreIrs2KO）的小鼠模型。我们报告了NesCreIrs2KO小鼠海马中NMDA受体依赖性突触可塑性的缺陷，并伴有元可塑性的丧失，即突触先前活动对突触可塑性的调节。这些可塑性变化与NMDA受体亚基NR1和PI3K途径下游靶点蛋白激酶Akt和GSK-3β的基础磷酸化减少有关。这些发现揭示了与神经元胰岛素信号的特定缺陷相关的认知缺陷的分子和细胞机制。
Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2). To study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO). We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β. These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling.
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影响因子：
5
作者：
Artola, Alain
通讯作者：
Artola, Alain
影响因子：
2.5
作者：
Fadool, DA;Tucker, K;Simmen, JA
通讯作者：
Simmen, JA
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Di Luca, M;Ruts, L;Gispen, WH
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Gispen, WH
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作者：
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通讯作者：
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作者：
HAVRANKOVA, J;ROTH, J
通讯作者：
ROTH, J