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

ABSTRACT: Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.

SUBMITTER: Besnard A

PROVIDER: S-EPMC7453932 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Besnard Antoine A Langberg Tomer T Levinson Sally S Chu Duong D Vicidomini Cinzia C Scobie Kimberly N KN Dwork Andrew J AJ Arango Victoria V Rosoklija Gorazd B GB Mann J John JJ Hen René R Leonardo E David ED Boldrini Maura M Sahay Amar A

Cell reports 20180601 11

Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiati ...[more]

PMID: 29898391

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Project description:Introduction: Bone morphogenetic protein (BMP) signaling is required for early forebrain development, however the role of this signalling pathway in later cortical patterning awaits careful mechanistic investigation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Aim: To investigate the expression and function of the BMP antagonist Gremlin1 (Grem1) in the developing mouse brain. Methods: The role of Grem1 in neuronal differentiation was assessed using neural stem cell (NSC) and progenitor cell culture ex vivo. Lineage tracing of Grem1 expressing cells in the fetal brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc cells from the dorsal telencephalon were FACS sorted into Grem1 positive and negative cells and bulk mRNA seq analysis of differentially expressed transcripts between the two cell populations was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox, Grem1Emx1 cKO, in which the Grem1 gene was deleted specifically in the dorsal telencephalon and assessed brain histology and mouse behavior. Results: Grem1 positive cells were located in the lower cortical plate and subplate at E14.5 and migrated towards the lateral ventricle. Grem1 cells expressed immature neuron markers, self-renewed and gave rise to layer Ⅴ and Ⅵ excitatory glutamatergic neurons. GREM1 expression also identifies a similar population of excitatory neurons in the developing human brain. Recombinant Grem1 treatment induced neural differentiation of NSCs in vitro, whilst Grem1Emx1 cKO animals had reduced thickness of the cortex, especially layers Ⅴ and Ⅵ. Behavioural tests revealed Grem1Emx1 cKO mice have impaired motor balance and fear sensitivity compared to littermate controls. Conclusion: Grem1 expression marks an early neuronal progenitor that gives rise to excitatory neurons in the embryonic mouse brain. This BMP antagonist functions to promote neural progenitor proliferation and neuronal differentiation.

Dataset Information

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

Publications

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

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