The psychiatric risk factor FKBP51 shapes stress resilience in astrocytes in a sex-specific manner

Major depressive disorder (MDD) is among the leading causes of illness induced disability worldwide, with women having a 1.6 times higher age-standardized rate of diagnosis than men. Despite this burden, currently prescribed antidepressants are suboptimal and the neurobiological basis of MDD is still poorly understood. The etiology of MDD encompasses both a genetic predisposition, among which the single nucleotide polymorphisms in the FKBP5 gene, as well as environmental factors, such as chronic stress, rendering an individual more or less susceptible to developing MDD. Our work aims at identifying new mechanisms of stress-induced dysfunction of neural circuits mediated through astrocytic glucocorticoid receptor and its binding partner, the FKBP51 protein. Previous findings in our lab revealed that FKBP5 deletion promoted stress resilience while altering MDD-associated behaviors and HPA axis activity in a region- and cell type–specific fashion. Mechanistically, FKBP51 involvement in cellular metabolic regulation may contribute to the downstream effects of aberrant glucocorticoid receptor signaling.

Astrocyte dysfunction has been shown to be involved in the pathophysiology of MDD as they are an important target for the glucocorticoid action in the brain. Specifically, previous studies have demonstrated that astrocytic glucocorticoid receptor deletion altered aversive memory formation and was associated with changes in the expression of genes involved in glucose metabolism. Additionally, transcriptomic studies of human brain samples from MDD patients consistently identified dysregulated astrocyte-specific genes involved in synaptic and metabolic functions. Thus, accumulating evidence suggests that astrocytes are key regulators connecting glucocorticoid receptor signaling to brain metabolism. However, FKBP51 signaling and its downstream metabolic effects upon stress remain comparatively underexplored in astrocytes.

In the current study, we first investigated the contribution of FKBP51 in behavioral alterations following stress exposure. After generating an in-house transgenic mouse line for conditional (tamoxifen-induced CreERT2), astrocyte-specific knockout, we exposed male and female mice to the chronic social defeat stress paradigm, which consists of exposing the experimental mice to an aggressive CD1 mouse for 21 consecutive days. Following this, we used the open-source DeepOpenField and DeepOF software to perform deep phenotyping of mouse social behavior, as well as commonly used behavior tests to assess anxiety, anhedonia and cognition. Our results revealed a male-specific alteration of anxiety-levels in whole brain knockout of astrocytic FKBP5 in mice exposed to social stress. Specifically, results from the elevated plus maze showed that the FKBP51-knockout male group showed a significant increase in the time spent in the open arms of the apparatus, which suggests a decrease in anxiety, whereas the females showed no significant difference. Additionally, the exploratory z-score obtained using the DeepOF software, is significantly elevated in the FKBP51-knockout male group compared to control, which suggests a protective effect on anxiety-related behaviors, consistent with the elevated plus maze data.

This preliminary study demonstrates a sex-specific protective role of whole brain knockout of the risk gene FKBP5, on anxiety-like behavior expressed by male mice.

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