RT Journal Article
SR Electronic
T1 The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0242-18.2019
DO 10.1523/ENEURO.0242-18.2019
VO 6
IS 1
A1 Laura J. Blair
A1 Marangelie Criado-Marrero
A1 Dali Zheng
A1 Xinming Wang
A1 Siddharth Kamath
A1 Bryce A. Nordhues
A1 Edwin J. Weeber
A1 Chad A. Dickey
YR 2019
UL http://www.eneuro.org/content/6/1/ENEURO.0242-18.2019.abstract
AB 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.