Loss of noradrenergic Fkbp5 disrupts social behavior and norepinephrine dynamics in the basolateral amygdala

Bordes, J.; Stont, L.; Bajaj, T.; Chang, S.; Ebert, T.; Miranda, L.; Schlegel, P.; Reinhardt, M.; Poehlmann, M.; Mecdad, Y.; Doeselaar, L. v.; Yang, H.; Kovarova, V.; Mitra, S.; De Angelis, M.; Muller-Myhsok, B.; Deussing, J. M.; Beyeler, A.; Gassen, N. C.; Schmidt, M. V.

doi:10.64898/2025.12.10.693477

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bioRxiv · 10.64898/2025.12.10.693477

Loss of noradrenergic Fkbp5 disrupts social behavior and norepinephrine dynamics in the basolateral amygdala

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Abstract

Social dysfunction is common in depression and varies with stress exposure and genetic risk. The current study identifies a cell-type specific role for Fkbp5, a glucocorticoid receptor co-chaperone, in noradrenergic neurons engaged during social stress. Acute social stress upregulated Fkbp5 in the locus coeruleus (LC), whereas repeated exposure attenuated this effect. Noradrenergic Fkbp5 deletion (Fkbp5Nat) increased pro-social behavior exclusively in male mice. In the basolateral amygdala (BLA), social interaction reduced norepinephrine (NE) turnover in wild-type but not Fkbp5Nat mice. Consistently, proteomics revealed mitochondrial/energy and synapse-related remodeling in BLA neurons. Miniscope imaging showed that behavior-locked NE transients in BLA were selectively blunted in Fkbp5Nat mice during interaction with outbred CD1 conspecifics, while same-strain C57BL/6N encounters preserved NE dynamics. Together, this study indicates that Fkbp5 tunes LC-BLA output to social salience in a sex- and context-dependent manner, suggesting a circuit-specific route to normalize social salience without broadly suppressing noradrenergic function.

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Bordes, J., Stont, L., Bajaj, T., Chang, S., Ebert, T., Miranda, L., Schlegel, P., Reinhardt, M., Poehlmann, M., Mecdad, Y., Doeselaar, L. v., Yang, H., Kovarova, V., Mitra, S., De Angelis, M., Muller-Myhsok, B., Deussing, J. M., Beyeler, A., Gassen, N. C., Schmidt, M. V.. 2025-12-12. Loss of noradrenergic Fkbp5 disrupts social behavior and norepinephrine dynamics in the basolateral amygdala. https://doi.org/10.64898/2025.12.10.693477

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