%0 Journal Article %A Laura J. Blair %A Marangelie Criado-Marrero %A Dali Zheng %A Xinming Wang %A Siddharth Kamath %A Bryce A. Nordhues %A Edwin J. Weeber %A Chad A. Dickey %T The disease-associated chaperone FKBP51 impairs cognitive function by accelerating AMPA receptor recycling %D 2019 %R 10.1523/ENEURO.0242-18.2019 %J eneuro %P ENEURO.0242-18.2019 %X 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 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 receptor. 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.Significance statement Candidate studies have identified a link between FKBP5 allelic variants and psychiatric disorders. Patients with these disorders often present with cognitive defects. FKBP5 variants have been correlated to decreased hippocampal volume, but a direct connection between FKBP5 and cognitive function has not been established. Here, we have found that mice with high levels of FKBP5 have altered reversal learning and memory, which may be through direct regulation of neuronal activity by regulating AMPA receptors. %U https://www.eneuro.org/content/eneuro/early/2019/02/12/ENEURO.0242-18.2019.full.pdf