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2019 Jan-Feb;6 (1):

The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling.

Laura J Blair, Marangelie Criado-Marrero, Dali Zheng, Xinming Wang, Siddharth Kamath, Bryce A Nordhues, Edwin J Weeber, Chad A Dickey
Author Information
  1. Laura J Blair: Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613. ORCID
  2. Marangelie Criado-Marrero: Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613. ORCID
  3. Dali Zheng: Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613.
  4. Xinming Wang: Department of Pharmacology and Physiology, University of South Florida, Byrd Institute, Tampa, FL 33613.
  5. Siddharth Kamath: Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613. ORCID
  6. Bryce A Nordhues: Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613.
  7. Edwin J Weeber: Department of Pharmacology and Physiology, University of South Florida, Byrd Institute, Tampa, FL 33613. ORCID
  8. Chad A Dickey: Department of Molecular Medicine, University of South Florida, Byrd Institute, Tampa, FL 33613.
PMID: 30963102 DOI: 10.1523/ENEURO.0242-18.2019

Abstract

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 .

Keywords

AMPA receptor FKBP5 Hsp90 chaperone

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Grants

  1. R01 MH103848/NIMH NIH HHS
  2. R01 NS073899/NINDS NIH HHS

MeSH Term

Animals
Cognition
Cognitive Dysfunction
Female
Humans
Long-Term Synaptic Depression
Male
Mice
Mice, 129 Strain
Mice, Transgenic
Protein Transport
Receptors, AMPA
Spatial Learning
Tacrolimus Binding Proteins

Chemicals

Receptors, AMPA
Tacrolimus Binding Proteins
tacrolimus binding protein 5
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 2

Word Cloud

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