Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder

Frodl, Thomas; Carballedo, Angela; Frey, Eva-Maria; O’Keane, Veronica; Skokauskas, Norbert; Morris, Derrek; Gill, M John; Hughes, Martin N.; Harkin, Andrew; Connor, Thomas J.

doi:10.1017/s0954579414000972

Cited by 20 publications

(14 citation statements)

References 47 publications

(65 reference statements)

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“…Anxiety, as well as major depressive disorder, is associated with decreased volume of the hippocampus 45 and DG. 46 We therefore estimated the volume of the DG granule cell layer in WT and Jnk1−/− mice using the Cavalieri estimator ( Figures 1l and m ). There was a trend towards increased volume in mice lacking Jnk1.…”

Section: Resultsmentioning

confidence: 99%

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

et al. 2016

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Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.

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Section: Resultsmentioning

confidence: 99%

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

et al. 2016

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“…Consistent with our results, some studies show HV reductions in adolescents at risk of developing MDD even before clinical manifestation of the disease. 37 , 38 Recent findings show associations between hippocampal volume abnormalities and several mechanisms involved in stress-related disorders and MDD, such as the messenger RNA expression of glucocorticoid inducible genes, 71 glucocorticoid receptor methylation, 72 genetic polymorphisms associated with variation in pro-inflammatory cytokine levels 73 and increased oxidative stress. 49 …”

Section: Discussionmentioning

confidence: 99%

Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder

et al. 2015

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Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13–18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.

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“…As can be seen, the vast majority of studies have focused on associations between depression and the FKBP5 genotype by investigating multiple single nucleotide polymorphisms (SNPs) throughout the gene (with a particular focus on the initially reported rs1360780). In general, it is currently hypothesized that depressed patients have increased basal FKBP51 levels [ 155 , 183 , 184 ] (although not observed in all populations [ 115 , 185 ]) that may be leading to a GR resistance [ 186 , 187 ]; alternatively, the basal promoter activity may be less relevant than the stress reactivity of the promoter that is shaped by genotype and epigenotype [ 6 ]. Moreover, the FKBP5 genotype has been reported to interact with the MDD diagnosis to predict structural neuroanatomical changes [ 116 , 188 , 189 , 190 ], as well as with prior lifetime trauma and/or stress to increase the risk for depression [ 191 , 192 , 193 , 194 ].…”

Section: Functions Of Fkbp51mentioning

confidence: 99%

The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease

Fries

Gassen

Rein

2017

IJMS

123

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Among the chaperones and co-chaperones regulating the glucocorticoid receptor (GR), FK506 binding protein (FKBP) 51 is the most intensely investigated across different disciplines. This review provides an update on the role of the different co-chaperones of Hsp70 and Hsp90 in the regulation of GR function. The development leading to the focus on FKBP51 is outlined. Further, a survey of the vast literature on the mechanism and function of FKBP51 is provided. This includes its structure and biochemical function, its regulation on different levels—transcription, post-transcription, and post-translation—and its function in signaling pathways. The evidence portraying FKBP51 as a scaffolding protein organizing protein complexes rather than a chaperone contributing to the folding of individual proteins is collated. Finally, FKBP51’s involvement in physiology and disease is outlined, and the promising efforts in developing drugs targeting FKBP51 are discussed.

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Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder

Cited by 20 publications

References 47 publications

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder

The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease

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