Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.

Autor: Codagnone MG; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.; APC Microbiome Ireland, University College Cork, Cork, Ireland.; Instituto de Biología Celular y Neurociencia 'de Robertis' IBCN (UBA-CONICET), Buenos Aires, Argentina., Kara N; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.; APC Microbiome Ireland, University College Cork, Cork, Ireland., Ratsika A; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.; APC Microbiome Ireland, University College Cork, Cork, Ireland., Levone BR; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland., van de Wouw M; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.; APC Microbiome Ireland, University College Cork, Cork, Ireland., Tan LA; Alkermes, Inc., Waltham, MA, USA., Cunningham JI; Alkermes, Inc., Waltham, MA, USA., Sanchez C; Alkermes, Inc., Waltham, MA, USA., Cryan JF; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. J.Cryan@ucc.ie.; APC Microbiome Ireland, University College Cork, Cork, Ireland. J.Cryan@ucc.ie., O'Leary OF; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. O.Oleary@ucc.ie.; APC Microbiome Ireland, University College Cork, Cork, Ireland. O.Oleary@ucc.ie.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Dec; Vol. 27 (12), pp. 4928-4938. Date of Electronic Publication: 2022 Sep 14.
DOI: 10.1038/s41380-022-01755-9
Abstrakt: Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.
(© 2022. The Author(s).)
Databáze: MEDLINE
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