Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus

Criado‐Marrero, Marangelie; Gebru, Niat T.; Gould, Lauren A.; Smith, Taylor M.; Kim, Sojeong; Blackburn, Roy J.; Dickey, Chad A.; Blair, Laura J.

doi:10.3390/ijms20112738

Cited by 37 publications

(40 citation statements)

References 47 publications

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“…Mice were placed individually in an empty square-shaped environment and allowed to explore for 5 min, as previously described [28]. Distance travelled and time spent in the center was tracked by video using ANY-maze software.…”

Section: Open Fieldmentioning

confidence: 99%

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Criado‐Marrero

Sabbagh

Jones

et al. 2020

Cells

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Tau dysfunction is common in several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Affective symptoms have often been associated with aberrant tau pathology and are commonly comorbid in patients with tauopathies, indicating a connection between tau functioning and mechanisms of depression. The current study investigated depression-like behavior in Mapt−/− mice, which contain a targeted deletion of the gene coding for tau. We show that 6-month Mapt−/− mice are resistant to depressive behaviors, as evidenced by decreased immobility time in the forced swim and tail suspension tests, as well as increased escape behavior in a learned helplessness task. Since depression has also been linked to deficient adult neurogenesis, we measured neurogenesis in the hippocampal dentate gyrus and subventricular zone using 5-bromo-2-deoxyuridine (BrdU) labeling. We found that neurogenesis is increased in the dentate gyrus of 14-month-old Mapt−/− brains compared to wild type, providing a potential mechanism for their behavioral phenotypes. In addition to the hippocampus, an upregulation of proteins involved in neurogenesis was observed in the frontal cortex and amygdala of the Mapt−/− mice using proteomic mass spectrometry. All together, these findings suggest that tau may have a role in the depressive symptoms observed in many neurodegenerative diseases and identify tau as a potential molecular target for treating depression.

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Section: Open Fieldmentioning

confidence: 99%

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Criado‐Marrero

Sabbagh

Jones

et al. 2020

Cells

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“…In the human population, there is a wide variation in perception of stressful challenges, and variation in physiological expression of stress. Single nucleotide polymorphisms (SNPs) within the FKBP5 gene locus have been reported to impact stress responsivity, and risk or resilience to psychiatric disorders (Appel et al., 2011; Binder, 2009; Criado‐Marrero et al., 2019; Liebermann et al., 2017; Wilker et al., 2014). Differential expression levels of FKBP5 have preclinically been shown to impact on stress‐coping behavior and the SNP rs1360780 was reported to profoundly influence stress coping, suggesting FKBP5 genotypes as one source of human variation (Ising et al., 2008; Touma et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Nold

Richter

Hengerer

et al. 2020

Eur J of Neuroscience

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The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism‐associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5‐humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5‐related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.

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“…It is ubiquitously expressed throughout the brain, but enriched in the hippocampus, hypothalamus, cortex, and amygdala 6 . Together with the heat shock protein 90, FKBP51 suppresses glucocorticoid receptor (GR) activity by decreasing the affinity of the GR to glucocorticoids and inhibiting nuclear transportation of the GR complex 7 . However, once the GR enters the nucleus, FKBP5 expression is upregulated via glucocorticoid response elements, thereby creating a short negative feedback loop that mediates hypothalamus–pituitary–adrenal (HPA) axis activity.…”

mentioning

confidence: 99%

Lack of FKBP51 Shapes Brain Structure and Connectivity in Male Mice

Engelhardt

Boulat

Czisch

et al. 2020

Magnetic Resonance Imaging

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Background Stress exposure as well as psychiatric disorders are often associated with abnormalities in brain structure or connectivity. The co‐chaperone FK506‐binding protein 51 (FKBP51) is a regulator of the stress system and is associated with a risk to develop stress‐related mental illnesses. Purpose To assess the effect of a general FKBP51 knockout on brain structure and connectivity in male mice. Study Type Animal study. Animal Model Two cohorts of FKBP51 knockout (51KO) and wildtype (WT) mice. The first cohort was comprised of n = 18 WT and n = 17 51KOs; second cohort n = 10 WT and n = 9 51KOs. Field Strength/Sequence 9.4T/3D gradient echo (VBM), DTI‐EPI (DTI). Assessment Voxel‐based morphometry (VBM) and diffusion tensor imaging (DTI). For VBM, all procedures were executed in SPM12. DTI: FMRIB Software Library (FSL) Tract Based Statistics (TBSS) were integrated within DTI‐TK, allowing the creation of a mean FA skeleton. A voxelwise statistical analysis was applied between WT and 51KO mice. Statistical Test Volumetric differences were collected at a threshold of P < 0.005, and only clusters surviving a familywise error correction on the cluster level (pFWE, cluster <0.05) were further considered. VBM data were analyzed using a two‐sample t‐test. The Threshold Free Cluster Enhancement (TFCE) method was used to derive uncorrected‐P statistical results at a P‐level of 0.01. Results The structural analysis revealed two clusters of significantly larger volumes in the hypothalamus, periaqueductal gray, and dorsal raphe region of WT animals. DTI measurements, however, demonstrated statistically higher fractional anisotropy (FA) values for 51KO animals in locations including the anterior commissure, fornix, and posterior commissure/superior colliculus commissure region. Data Conclusion This study used in vivo structural MRI and DTI to demonstrate that a lack of FKBP51 leads to alterations in brain architecture and connectivity in male mice. These findings are of particular translational relevance for our understanding of the neuroanatomy underlying the interaction of FKBP5 genetic status, stress susceptibility, and psychiatric disorders. Level of Evidence 1 Technical Efficacy Stage 1

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Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus

Cited by 37 publications

References 47 publications

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Lack of FKBP51 Shapes Brain Structure and Connectivity in Male Mice

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