Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses

Besnard, Antoine; Langberg, Tomer; Levinson, Sally; Chu, Duong; Vicidomini, Cinzia; Scobie, Kimberly N.; Dwork, Andrew J.; Arango, Victoria; Rosoklija, Gorazd; Mann, J. John; Hen, René; Leonardo, E. David; Boldrini, Maura; Sahay, Amar

doi:10.1016/j.celrep.2018.05.040

“…This is consistent with a recent report that injection of cortisol into eggs leads to increased neurogenesis in the larval brain 10 . In this regard it is interesting that klf9 is a stress-responsive gene that regulates neural differentiation and plasticity 35,46 . The long-term dysregulation of the HPA/I axis caused by early life exposure to chronic stress and/or chronically elevated cortisol suggests that the exposure perturbs brain development and activity.…”

Section: Scientific Reports |mentioning

confidence: 99%

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

Gans

¹

,

Hartig

²

,

Zhu

³

et al. 2020

Sci Rep

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The zebrafish has recently emerged as a model system for investigating the developmental roles of glucocorticoid signaling and the mechanisms underlying glucocorticoid-induced developmental programming. To assess the role of the Glucocorticoid Receptor (GR) in such programming, we used CRISPR-Cas9 to produce a new frameshift mutation, GR 369-, which eliminates all potential in-frame initiation codons upstream of the DNA binding domain. Using RNA-seq to ask how this mutation affects the larval transcriptome under both normal conditions and with chronic cortisol treatment, we find that GR mediates most of the effects of the treatment, and paradoxically, that the transcriptome of cortisol-treated larvae is more like that of larvae lacking a GR than that of larvae with a GR, suggesting that the cortisol-treated larvae develop GR resistance. The one transcriptional regulator that was both underexpressed in GR 369larvae and consistently overexpressed in cortisol-treated larvae was klf9. We therefore used CRISPR-Cas9-mediated mutation of klf9 and RNA-seq to assess Klf9-dependent gene expression in both normal and cortisol-treated larvae. Our results indicate that Klf9 contributes significantly to the transcriptomic response to chronic cortisol exposure, mediating the upregulation of proinflammatory genes that we reported previously. The vertebrate hypothalamus-pituitary-adrenal (HPA) axis orchestrates physiological, behavioral, and metabolic adjustments required for homeostasis, by dynamically regulating production and secretion of adrenal steroids known as glucocorticoids. In humans the primary glucocorticoid is cortisol, the biological activity of which is mediated by two regulatory proteins in the nuclear receptor family, the ubiquitous glucocorticoid receptor (GR) and the more tissue-restricted mineralocorticoid receptor (MR). The GR binds cortisol less avidly than the MR and is thus more dynamically regulated over the normal physiological range of cortisol fluctuations 1,2. The GR and MR function both as transcription factors and as non-nuclear signaling proteins, including in the central nervous system where both proteins are highly expressed 1-5. Given that the GR is more widely expressed and more dynamically regulated by cortisol, it is generally thought to be the principal mediator of cortisolinduced genomic responses to circadian rhythms and acute stress 5. An important question for understanding GR function is what downstream transcriptional regulatory genes does it regulate, and to what end? Answering this question is not only important for understanding the physiological function and regulation of the GR, but also for deciphering the gene regulatory networks that orchestrate adaptive developmental programming in response to chronic glucocorticoid exposure such as occurs with chronic early life stress 6. The zebrafish has recently emerged as a model system well-suited to investigating the developmental functions of glucocorticoid signaling and mechanisms underlying stress-induced developmental programming 7-...

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“…PSD-95 is believed to be a key regulator of dendritic morphology and when overexpressed it adversely affects dendritic morphology and complexity (Charych et al 2006). We extended these findings and proved that continuous lithium treatment followed by a period without lithium acts positively on dendritic maturation and complexity, which is arguably a morphometric parameter that has important functional implications in memory function and anti-stress mechanisms (Besnard et al 2018). We hypothesized that this is attributable to key regulatory proteins involved in cytoskeletal rearrangements (Tppp) and synaptic transmission (GAD65).…”

Section: Identification Of Mechanismsmentioning

confidence: 74%

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

Zanni

¹

,

Goto

²

,

Gaudenzi

³

et al. 2019

Preprint

0

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Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, proneurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li 2 CO 3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

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“…This is consistent with a recent report that injection of cortisol into eggs leads to increased neurogenesis in the larval brain 24 . In this regard it is interesting that klf9 is a stress-responsive gene that regulates neural differentiation and plasticity 8,19 . The long-term dysregulation of the HPA/I axis caused by early life exposure to chronic stress and/or chronically elevated cortisol suggests that the exposure perturbs brain development and activity.…”

Section: Discussionmentioning

confidence: 99%

“…In epidermis many of the genes repressed by Klf9 are also activated by the GR 6 . It was recently shown that klf9 is upregulated in mouse hippocampus in response to the onset of chronic stress, and blocking that upregulation prevents chronic stress-induced pathologies 19 . In the same study it was also shown that hippocampuses of women with major depression were found to overexpress KLF9 19 .…”

Section: Introductionmentioning

confidence: 99%

“…It was recently shown that klf9 is upregulated in mouse hippocampus in response to the onset of chronic stress, and blocking that upregulation prevents chronic stress-induced pathologies 19 . In the same study it was also shown that hippocampuses of women with major depression were found to overexpress KLF9 19 . Finally, it was recently discovered that Dexamethasone-induced upregulation of Klf9 promotes hepatic gluconeogenesis and hyperglycemia in mice 20 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

Gans

¹

,

Hartig

²

,

Zhu

³

et al. 2019

Preprint

View full text Add to dashboard Cite

The zebrafish has recently emerged as a model system for investigating the developmental roles of glucocorticoid signaling and the mechanisms underlying glucocorticoid-induced developmental programming. To assess the role of the Glucocorticoid Receptor (GR) in such programming, we used CRISPR-Cas9 to produce a new frameshift mutation, GR 369-, which eliminates all potential in-frame initiation codons upstream of the DNA binding domain. Using RNA-seq to ask how this mutation affects the larval transcriptome under both normal conditions and with chronic cortisol treatment, we find that GR mediates most of the effects of the treatment, and paradoxically, that the transcriptome of cortisol-treated larvae is more like that of larvae lacking a GR than that of larvae with a GR, suggesting that the cortisol-treated larvae develop GR resistance. The one transcriptional regulator that was both underexpressed in GR 369larvae and consistently overexpressed in cortisol-treated larvae was klf9. We therefore used CRISPR-Cas9-mediated mutation of klf9 and RNA-seq to assess Klf9-dependent gene expression in both normal and cortisol-treated larvae. Our results indicate that Klf9 contributes significantly to the transcriptomic response to chronic cortisol exposure, mediating the upregulation of proinflammatory genes that we reported previously.

show abstract

Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses

Cited by 33 publications

References 61 publications

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

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