Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613.
Department of Pharmacology and Physiology, University of South Florida, Byrd Institute, Tampa, FL 33613.
eNeuro. 2019 Mar 1;6(1). doi: 10.1523/ENEURO.0242-18.2019. eCollection 2019 Jan-Feb.
Increased expression of the FK506-binding protein 5 () 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 remains unclear. We generated a novel transgenic mouse to selectively overexpress 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 .
FK506 结合蛋白 5 () 基因的表达增加与许多疾病有关，但与精神疾病的关系最为密切。许多精神疾病表现为痴呆和其他认知缺陷，但这些问题与 变化之间的直接联系尚不清楚。我们生成了一种新型转基因小鼠，选择性地在皮质边缘系统中过表达编码 FKBP51 蛋白的 ，这对总体重、运动能力或一般焦虑没有明显影响。相反，我们发现 FKBP51 的过表达会损害长时程抑郁 (LTD) 以及空间反转学习和记忆，表明其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 受体的结合，这伴随着 AMPA 回收速度的加快。通过这种方式，伴侣蛋白系统在 AMPA 受体运输的分类决策中至关重要。伴侣蛋白系统的失衡可能表现在抑制性学习和认知功能的损伤。这些发现揭示了学习和记忆的一个意想不到的重要机制，它受精神疾病风险因素 的控制。
