The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling
The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling
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DOI：
10.1523/eneuro.0242-18.2019
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发表时间：
2019-01-01
期刊：
影响因子：
3.4
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Blair, Laura J.;Criado-Marrero, Marangelie;Dickey, Chad A.
FK506结合蛋白5(FKBP5)基因的高表达与许多疾病有关，但最显著的是与精神疾病有关。这些精神障碍中的许多都存在痴呆症和其他认知缺陷，但这些问题与FKBP5变化之间的直接联系尚不清楚。我们创造了一种新型的转基因小鼠，在皮质边缘系统中选择性地过度表达FKBP5，它编码FKBP51蛋白，对总体重、运动能力或一般焦虑没有明显影响。相反，我们发现FKBP51的过度表达损害了长期抑郁(LTD)以及空间反转学习和记忆，这表明FKBP51在谷氨酸受体调节中发挥作用。事实上，FKBP51改变了热休克蛋白90(Hsp90)与AMPA受体的联系，这伴随着AMPA循环的加速。在这种情况下，伴侣系统在AMPA受体贩运的分类决策中至关重要。伴侣系统的失衡可能表现为抑制性学习和认知功能的损害。这些发现揭示了一种意想不到的、基本的学习和记忆机制，这种机制由精神风险因素FKBP5控制。
Increased expression of the FK506-binding protein 5 (FKBP5) gene has been associated with a number of diseases, but most prominently in connection to psychiatric illnesses. Many of these psychiatric disorders present with dementia and other cognitive deficits, but a direct connection between these issues and alterations in FKBP5 remains unclear. We generated a novel transgenic mouse to selectively overexpress FKBP5, which encodes the FKBP51 protein, in the corticolimbic system, which had no overt effects on gross body weight, motor ability, or general anxiety. Instead, we found that overexpression of FKBP51 impaired long-term depression (LTD) as well as spatial reversal learning and memory, suggesting a role in glutamate receptor regulation. Indeed, FKBP51 altered the association of heat-shock protein 90 (Hsp90) with AMPA receptors, which was accompanied by an accelerated rate of AMPA recycling. In this way, the chaperone system is critical in triage decisions for AMPA receptor trafficking. Imbalance in the chaperone system may manifest in impairments in both inhibitory learning and cognitive function. These findings uncover an unexpected and essential mechanism for learning and memory that is controlled by the psychiatric risk factor FKBP5.