Prenatal glucocorticoid exposure selectively impairs neuroligin 1-dependent neurogenesis by suppressing astrocytic FGF2–neuronal FGFR1 axis

Abstract

Exposure to maternal stress irreversibly impairs neurogenesis of offspring by inducing life-long effects on interaction between neurons and glia under raging differentiation process, culminating in cognitive and neuropsychiatric abnormalities in adulthood. We identified that prenatal exposure to stress-responsive hormone glucocorticoid impaired neurogenesis and induced abnormal behaviors in ICR mice. Then, we used human induced pluripotent stem cell (iPSC)-derived neural stem cell (NSC) to investigate how neurogenesis deficits occur. Following glucocorticoid treatment, NSC-derived astrocytes were found to be A1-like neurotoxic astrocytes. Moreover, cortisol-treated astrocytic conditioned media (ACM) then specifically downregulated AMPA receptor-mediated glutamatergic synaptic formation and transmission in differentiating neurons, by inhibiting localization of ionotropic glutamate receptor (GluR)1/2 into synapses. We then revealed that downregulated astrocytic fibroblast growth factor 2 (FGF2) and nuclear fibroblast growth factor receptor 1 (FGFR1) of neurons are key pathogenic factors for reducing glutamatergic synaptogenesis. We further confirmed that cortisol-treated ACM specifically decreased the binding of neuronal FGFR1 to the synaptogenic NLGN1 promoter, but this was reversed by FGFR1 restoration. Upregulation of neuroligin 1, which is important in scaffolding GluR1/2 into the postsynaptic compartment, eventually normalized glutamatergic synaptogenesis and subsequent neurogenesis. Moreover, pretreatment of FGF2 elevated neuroligin 1 expression and trafficking of GluR1/2 into the postsynaptic compartment of mice exposed to prenatal corticosterone, improving spatial memory and depression/anxiety-like behaviors. In conclusion, we identified neuroligin 1 restoration by astrocytic FGF2 and its downstream neuronal nuclear FGFR1 as a critical target for preventing prenatal stress-induced dysfunction in glutamatergic synaptogenesis, which recovered both neurogenesis and hippocampal-related behaviors.

FGF9 is required for Purkinje cell development and function in the cerebellum

“… 9 , 10 , 11 It has shown that FGF2 secreted by astrocytes interacts with neuronal FGFR1 to maintain synaptogenesis for supporting prenatal neurogenesis. 12 FGF8 transcripts observed in the EGL at E16.5 and P0 mice are significantly decreased at Postnatal 7 days. Moreover, mutation in regulator of Gli signaling dramatically accelerates FGF8 expression in EGL.…”

Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR

“…Beads were washed three times with PBST and eluted with 20 mM glycine buffer (pH 2.0) for 5 min. Then, 1 M phosphate buffer and laemmli sample buffer were added to the samples following the protocol from our previous research [ 33 ]. Protein analysis was conducted by western blot where anti-mouse or rabbit IgG antibody was used as a negative control.…”

In vitro modeling of glucocorticoid mechanisms in stress-related mental disorders: Current challenges and future perspectives

“…Moreover, many of the differentiation protocols to obtain neuronal cultures are heterogeneous in cell types and many include glial cells ( Volpato and Webber, 2020 ). This may in itself influence the response of neurons to GCs knowing that glial cells such as astrocytes have also been shown to respond to GCs in vitro ( Heard et al, 2021 ; Choi et al, 2022 ). Additionally, a study by Cruceanu et al (2022) demonstrated cell-type specific responses to GCs in vitro , with differential-responses between different types of neural progenitors and neurons ( Notaras et al, 2021 ).…”

“…Investigating stress mechanisms in vitro (as most molecular biology assays) is a highly reductionist approach ( Regenmortel, 2004 ) to understanding stress, its underlying processes, and the mechanisms of SRMDs more broadly. That being said, in vitro stress models aim to investigate underlying mechanisms involved in the stress response, as a reaction to exposure to particular stress hormones, with the most studied hormone being GCs ( Bhargava et al, 2002 ; Kim et al, 2004 ; Cote-Vélez et al, 2005 ; Numakawa et al, 2009 ; Anacker et al, 2013 ; Bharti et al, 2018 ; Nürnberg et al, 2018 ; Yeo et al, 2019 ; Krontira et al, 2020 ; Cruceanu et al, 2021 ; Heard et al, 2021 ; Choi et al, 2022 ). In essence, one would assume that investigating effects of GCs in vitro seems straightforward.…”