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FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice via a Tcf4-mediated pathway

ABSTRACT: Early life stress (ELS) has often been described as a risk factor for developing psychiatric disease. However, moderate exposure to ELS can also lead to stress inoculation and consequently adaptive changes on brain and behavior. Moreover, the FKBP5 gene, encoding the FKBP51 co-chaperone, has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. However, the underlying mechanisms behind the interaction of FKBP51 and moderate ELS exposure are still not completely understood and particularly data in the female sex are scarce. In this study, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of moderate ELS was investigated in both sexes, by using the Fkbp5Nex conditional knockout line. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in in Fkbp5Nexx wild-type mice. Interactive effects of FKBP51 in glutamatergic forebrain neurons and moderate ELS exposure in female mice were also reflected on brain volume of different cortical regions, the subiculum and white matter structures. Furthermore, interactive effects were observed for structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of these interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the moderate ELS exposure. Taken together, this study shows that FKBP51 in glutamatergic forebrain neurons mediates adaptive effects of moderate ELS exposure on emotional regulation, cognitive behavior and neuronal structure and function. Moreover, it proposes TCF4 as an underlying target that drives the FKBP51-mediated effects of moderate ELS on brain and behavior.

ORGANISM(S): Mus musculus

PROVIDER: GSE256468 | GEO | 2024/02/26

REPOSITORIES: GEO

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Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters, peptides and their receptors, and thus having long-lasting behavioral effects. Some of these changes have been observed in animal experiments, others also in humans prenatally exposed to synthetic corticosteroids. Here, we focused on transcriptomic changes within the ARC of rats prenatally exposed to either betamethasone or saline. The expression of transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. Total of 18,094 unigenes were quantified in the hypothalamic ARC of P14 male and female rats prenatally exposed to betametasone used in this experiment. Out of these genes, Kyoto Encyclopedia for Genes and Genomes (http://www.genome.jp) selected 112 for the dopaminergic synapse, 75 for the GABAergic and 97 for the glutamatergic synapse. We further analyzed composition, topology and modulatory networks of the genomic fabric of the dopaminergic, GABAergic, and glutamatergic synapse (the transcriptome of the most interconnected and stably expressed gene network responsible for specific transmission). Finally we investigated the M-bM-^@M-^\transcriptomic landscapeM-bM-^@M-^] of the GSF in the ARC of P14 males (M) and females (F) prenatally (G15) exposed to betamethasone (B) or saline (S). We combined in one measure (PWR = Pair-Wise Relevance) expression levels, controls and coordination of all pairs that can be formed by synapse genes with the other synapse genes, higher PWRs indicating larger influence of that gene pair to the fabric modulation. We found that prenatal exposure to betamethasone caused sex-dependent changes in the dopaminergic/GABA/glutamatergic synapse genes:. In males, 10 dopaminergic (9%), 4 GABAergic (5%) and 5 glutamatergic synapse genes (5%) were down-regulated. While in females, 9 dopaminergic (8%), 3 GABAergic (4%) and 6 glutamatergic (6%) synapse genes were downregulated. The data indicate that in both sexes the dopaminergic synapse was the most affected. In contrast, in control animals, no significant differences between male and female were present in these synapse genes. Since the most noticeable transcritpomic changes were found in the transcriptome of DA glutamatergic synapse, we investigated the expression of tyrosine-hydroxylase (TH) NMDA receptor subunits in the ARC. The western blot analyses and immunohistochemistry confirmed the sex-specific differences between prenatally betamethasone-exposed and saline-exposed P15 rats. Accordingly to the changes in gene expression, prenatal exposure to synthetic corticosteroids was associated with postnatal changes in behavior and susceptibility to certain types of seizures. While we did not find any significant impairements in normal behavioral patterns (open field activity), there was a sex-specific change in the novel object recognition test. We found that behavioral lateralization in females is lost after prenatal betamethasone exposure and both male and female prenatally betamethasone exposed rats were avoiding novelty. This trait is similar to children with autism and suggests that certain elements of autistic behaviors can be present after prenatal exposure to synthetic corticosteroids. Additionally, there were changes in the search patterns in the Morris water maze as well as in the Barnes maze. In conclusion, our work is consistent with findings of profound reprogramming changes in the brain after prenatal corticosteroid exposure associated with alterations cognitive functions and seizure susceptibility. Two-sexes (M, F) x two-condition (B = betamethasone prenataly exposed vs S = saline prenataly exposed) experiment. Biological replicates: 4 MS, 4 FS, 4 MB, 4 FB.

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FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice via a Tcf4-mediated pathway

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