Physiological and Circadian Outcomes of FKBP5 Imbalance: Insights from Two Models

Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Laura J. Blair, Ph.D.

Co-Major Professor

Danielle Gulick, Ph.D.

Committee Member

Vladimir Uversky, Ph.D., D.Sc.

Committee Member

Gopal Thinakaran, Ph.D.

Committee Member

Umit Kayisli, M.Sc., Ph.D.

Keywords

FK506 binding protein 5, neuropsychiatric disorders, stress

Abstract

Circadian rhythms are crucial in regulating various physiological processes, including mood regulation, and disruptions in these rhythms have been linked to several neuropsychiatric disorders, such as depression, bipolar disorder, and schizophrenia. FKBP51, a protein involved in stress responses and glucocorticoid receptor function has emerged as a potential regulator of the circadian clock. FKBP51’s interaction with glucocorticoid receptors impacts the transcriptional regulation of circadian-related genes. In recent years, FKBP51 has been associated with genetic and epigenetic alterations in neuropsychiatric disorders, highlighting its potential as a target for intervention. The heterogeneity associated with neuropsychiatric disorders arises from a combination of genetic, environmental, and biological factors that have posed a significant challenge in generating effective interventions. This interplay between circadian rhythms and neuropsychiatric disorders underscores the importance of investigating potential therapeutic targets like FKBP51. The work described in this dissertation provides a comprehensive overview of the genetic mouse models of FKBP5 (Fkbp5-/-, conditional knockout, overexpression, and humanized mouse models) and their impact on several biological processes including metabolism, inflammation, stress response, cognition, and sleep. Next, we leverage two distinct mouse models of FKBP51, one that lacks FKBP51 and one that overexpresses FKBP51, to characterize and understand how imbalances in FKBP51 can alter general homeostasis by influencing molecular and phenotypic changes, including the circadian machinery. The findings shed light on the molecular mechanisms by which FKBP51 influences the circadian clock, neuroinflammation, and synaptic function in an age- and sex-dependent manner. Lack of FKBP51 did not significantly alter the overall circadian rhythmicity, but sex-specific effects in the presence of acute stress were measured. These mice also exhibited modest molecular changes in specific clock proteins in the hippocampus and amygdala. Further analysis revealed changes in protein expression related to ubiquitination, synaptic integrity, and various signaling pathways in the hippocampus and amygdala of mice lacking FKBP51. Conversely, mice overexpressing human FKBP5 (rTgFKBP5) displayed improved rhythm amplitude and reduced rhythm fragmentation, with notable sex differences. Female rTgFKBP5 mice exhibited more dynamic daily fluctuations in the stress hormone, corticosterone, with a heightened response to acute stress. Additionally, time-of-day-dependent changes in core clock protein expression were observed in specific brain regions of these mice. These findings suggest that FKBP51 can impact circadian rhythms, stress responses, and related molecular pathways in the brain, with evidence for age- and sex-related differences. These findings suggest that targeting FKBP51 with inhibitors could offer a promising avenue for modulating circadian rhythms and associated molecular pathways, potentially providing novel interventions for neuropsychiatric disorders.

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