The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice

Anderzhanova, Elmira; Hafner, Kathrin; Genewsky, Andreas; Soliman, A. A.; Pöhlmann, Max L.; Schmidt, Mathias; Blum, Robert; Wotjak, Carsten T.; Gassen, Nils C.

doi:10.1016/j.ynstr.2020.100239

Cited by 22 publications

(17 citation statements)

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“…Surgeries were performed as described previously in Anderzhanova et al 53 and in Anderzhanova et al 54 under 2% isoflurane in oxygen (Abbot, India), Metacam ® 0.5 mg/kg, s.c (Boehringer Ingelheim GmbH, Germany), and Novalgine 200 mg/kg, s.c. (Sanofi-Aventis, Germany) systemic anesthesia and analgesia. Lidocaine 2% (Xylocaine, AstraZeneca) was used for local anesthesia.…”

Section: Methodsmentioning

confidence: 99%

Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

et al. 2021

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The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy via the stress-responsive co-chaperone FK506-binding protein 51. We identify the matrix metalloproteinase 9 (MMP9) as one of the proteins secreted in response to stress. Using cellular assays and in vivo microdialysis, we further find that stress-enhanced MMP9 secretion increases the cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF). BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders.

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Section: Methodsmentioning

confidence: 99%

Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

et al. 2021

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“…Possible impact of FKBP5 on synaptic transmission in younger individuals is consistent with the neuronal expression pattern reported above as well as direct protein/protein interaction partners and downstream targets of FKBP51 that have been shown to impact neuronal function. These include brain-derived neurotrophic factor (BDNF) 32 , glycogen synthase kinase 3ß (GSK3ß) 33 , calcineurin 34, , synapsin 36 , protein kinase B/Akt 37 and AMPA receptors 27 . In older individuals, we observed co-expression of FKBP5 with gene transcripts in pathways related to neuroinflammation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Associations of psychiatric disease and aging onFKBP5expression converge on cortical supragranular neurons

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Arloth

Martinelli

et al. 2021

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Deducing genes capable of classifying biologically-distinct psychiatric subtypes, and their targets for treatment, is a priority approach in psychiatry. FKBP5 is one such gene with strong evidence of utility to delineate a trans-diagnostic psychiatric subtype. Yet how brain-expressed FKBP5 is affected in psychiatric disorders in humans is not fully understood and critical for propelling FKBP5-targeting treatment development. We performed a large-scale postmortem study (n=895) of FKBP5 using dorsolateral prefrontal cortex samples derived from individuals with severe psychiatric disorders with a comprehensive battery of bulk/single-cell omics and histological analyses. We observed consistently heightened FKBP5 mRNA and protein in psychopathology, moderated by genotype and age, and accompanied by DNA methylation changes in key enhancers. These effects were most prominent in superficial-layer pyramidal cells. Heightened FKBP5 was also differentially associated with downstream pathways according to age, being specifically associated with synaptic transmission in early adulthood, and neuroinflammation and neurodegeneration in later life.

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“…Targets downstream of glutamate receptor activation. (2R,6R)-and (2S,6S)-HNK have been shown to modulate the activity of targets downstream of glutamate receptors, including BDNF (Zanos et al, 2016;Fukumoto et al, 2019;Lumsden et al, 2019;Anderzhanova et al, 2020) and mTOR (Paul et al, 2014;Fukumoto et al, 2019;Lumsden et al, 2019). These effects are summarized in Table 4.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…Numerous studies have reported that (2R,6R)-HNK increases a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-dependent synaptic transmission, in part by increasing glutamate release (Pham et al, 2018;Riggs et al, 2019) and AMPAR expression (Zanos et al, 2016;Ho et al, 2018;Shaffer et al, 2019). There is also evidence indicating that the effects of (2R,6R)-HNK converge with metabotropic glutamate (mGlu) receptor signaling (Wray et al, 2019;Zanos et al, 2019b) and activate mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) signaling (Paul et al, 2014;Zanos et al, 2016;Fred et al, 2019;Fukumoto et al, 2019;Lumsden et al, 2019;Aguilar-Valles et al, 2020;Anderzhanova et al, 2020). There are additional reports demonstrating that (2R,6R)-HNK increases the release of other neurotransmitters, including serotonin and norepinephrine (Ago et al, 2019), and promotes structural plasticity via dendritic outgrowth (Cavalleri et al, 2018;Collo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

et al. 2021

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The following authors declare competing financial interests: R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro-and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.M., C.T., C.A.Z., and T.G. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.A.Z., and C.T. have assigned their patent rights to the United States government but will share a percentage of any royalties that may be received by the government. P.Z. and T.G. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7, LLC, during the preceding 3 years. All other authors declare no competing interests.

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The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice

Cited by 22 publications

References 56 publications

Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

Associations of psychiatric disease and aging onFKBP5expression converge on cortical supragranular neurons

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

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