Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity.
Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity.
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作者：
Grillo CA;Piroli GG;Lawrence RC;Wrighten SA;Green AJ;Wilson SP;Sakai RR;Kelly SJ;Wilson MA;Mott DD;Reagan LP
胰岛素受体 (IR) 在中枢神经系统的离散神经元群中表达，包括海马体。为了阐明海马 IR 独立于代谢功能的功能作用，我们使用表达 IR 反义序列 (LV-IRAS) 的慢病毒载体生成了海马特异性胰岛素抵抗模型。 LV-IRAS 有效下调大鼠海马中 IR 的表达，而不影响体重、肥胖或外周葡萄糖稳态。然而，经 LV-IRAS 治疗的大鼠的海马神经可塑性受损。高频刺激在 LV 对照大鼠的脑切片中引起强烈的长时程增强 (LTP)，但未能在 LV-IRAS 治疗的大鼠中引起 LTP。 LV-IRAS 大鼠海马中的 GluN2B 亚基水平以及 GluA1 磷酸化基础水平均降低。此外，突触传递的这些缺陷与空间学习的损伤有关。我们认为谷氨酸受体亚基的表达和磷酸化的改变是 LTP 改变的基础，并且这些改变是海马依赖性学习受损的原因。重要的是，这些学习缺陷与在糖尿病患者中观察到的复杂任务表现的损害惊人地相似，这强化了这样的假设：海马胰岛素抵抗是独立于血糖控制的认知缺陷的关键介质。
Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS–treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS–treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control.