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Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.

ABSTRACT: Anesthesia recovery is critical for resuming normal physiological and neuronal functions; however, the mechanisms involved remain elusive. Here, we identify a female-selective corticosterone-mediated microglia-neuron interaction in vivo during ketamine anesthesia recovery, absent in males. This microglia-neuron interaction induces plastic and functional neuronal changes, as evidenced by increased spine density and mEPSC frequency, which is occluded upon microglia depletion. We show that this process is driven through upregulation of the stress-responsive co-chaperone Fkbp5 mRNA and its protein, FKBP51, in female microglia. Fkbp5/FKBP51 is a key intermediary in a corticosteroid-induced stress response, and its involvement points towards a critical interface between endocrine signaling and microglia. Thus, to counteract the observed KXA-mediated corticosterone increase in the blood, we remove the primary source of corticosterone through adrenalectomy. Close microglia-neuron interaction was absent, but was reinstated after corticosterone injection. Our findings offer a new mechanism of microglia-mediated neuronal plasticity during anesthesia recovery, which is mediated through corticosterone, enhancing our understanding of sex differences in brain function.

ORGANISM(S): Mus musculus

PROVIDER: GSE298669 | GEO | 2026/06/25

REPOSITORIES: GEO

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Project description: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.

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Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.

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