The Impact of FKBP5 Deficiency in Glucocorticoid Receptor Mediated Regulation of Synaptic Transmission in the Medial Prefrontal Cortex

Abstract

Exposure to stress activates glucocorticoid receptors in the brain and facilitates the onset of multitude psychiatric disorders. It has been shown that FK506 binding protein 51 (FKBP5) expression increases during glucocorticoid receptor (GR) activation in various brain regions including the medial prefrontal cortex (mPFC). FKBP5 knockout (KO) mice are reported to be resilient to stress, however, it remains uninvestigated whether FKBP5 loss affects neurotransmission and if so, what the functional consequences are. Here, we examined the impact of FKBP5 deletion in synaptic transmission of the mPFC. We found that GR activation significantly decreased excitatory neurotransmission in the mPFC, which was completely abolished upon FKBP5 deletion, in consistent with behavioral resilience observed in FKBP5 KO mice. Even though FKBP5 loss has minimal impact on neural excitability, we found that FKBP5 deletion distorts the excitatory/inhibitory balance in the mPFC. Our study suggests that FKBP5 deficiency leads to the mPFC insensitive to GR activation and provides a neurophysiological explanation for how FKBP5 deficiency may mediate stress resilience.

Keywords: FKBP5; depressive disorders; glucocorticoid receptor; infralimbic cortex; prelimbic cortex; synaptic transmission.