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

Highlights

• FKBP5 deficiency increases inhibitory spontaneous transmission with minimal changes in excitatory transmission in the mPFC.

• FKBP5 loss blocks the effect of GR activation on spontaneous neurotransmission.

• FKBP5 expression levels are different between the PL and the IL but minimal physiological difference was observed.

• Deletion of FKBP5 alters the overall E/I balance of the mPFC towards greater inhibition.

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.

Introduction

Stress is a well-established risk factor hosting a number of psychiatric disorders, including major depression (Kendler et al., 1999). It is known that stress increases endogenous glucocorticoid levels and glucocorticoid receptor (GR) activation in various brain areas including the medial prefrontal cortex (mPFC), a key brain area controlling cognition and emotion thereby contributing to mediate depressive-like behaviors (McEwen, 2007, McKlveen et al., 2013). FK506 binding protein 51 (FKBP5), a prolyl isomerase, is known to regulate the sensitivity of GR via decreasing the binding affinity of glucocorticoid to GRs thus inhibiting translocation of activated GR (Denny et al., 2000). FKBP5 expression levels vary depending on tissue types as well as among individuals and FKBP5 induction has been proposed as a confidential indication of GR sensitivity (Vermeer et al., 2003, Kelly et al., 2012, Menke et al., 2012). Recent studies reported that polymorphisms of FKBP5 genes determine GR sensitivity (Binder et al., 2004, Ellsworth et al., 2013, Klengel et al., 2013). For example, the rs1360780 T allele is associated with an increase in GR-induced FKBP5 upregulation compared to alternate C allele. In preclinical studies, FKBP5 deficient mice showed resilient to stress and conditioned fear (Touma et al., 2011, Criado-Marrero et al., 2017).

The mPFC expresses FKBP5 proteins abundantly (Criado-Marrero et al., 2017). Stressful events and/or fear conditioning increase endogenous glucocorticoid levels, which in turn activate GRs and induce FKBP5 protein expression in the mPFC (Guidotti et al., 2013, Criado-Marrero et al., 2017). The levels of FKBP5 protein was shown to be reversed by antidepressants treatment (Guidotti et al., 2013). In case of FKBP5-lacking mice, acute restraint stress exposure failed to increase endogenous glucocorticoid level thereby decreased depressive behaviors were observed (Touma et al., 2011, Criado-Marrero et al., 2017).

FKBP5 expression patterns are different between the prelimbic cortex (PL) and infralimbic cortex (IL) of the mPFC. Generally more FKBP5 proteins are expressed in the PL, however, fear conditioning increases FKPB5 expression only in the IL. Knockdown of FKBP5 in the IL (but not the PL) could block the freezing response after fear conditioning, suggesting sub-region specific roles of FKBP5 (Criado-Marrero et al., 2017).

In the mPFC, acute stress exposure or brief GR activation were shown to increase efficacy of excitatory synaptic transmission while decrease inhibitory synaptic transmission (Yuen et al., 2009, Hill et al., 2011), whereas chronic stress was reported to decrease efficacy of excitatory synaptic transmission while increase inhibitory synaptic transmission (Yuen et al., 2012, McKlveen et al., 2016). Antidepressant treatment successfully reversed these stress-induced synaptic alterations (Yuen et al., 2009). Thus, GR activation seems to regulate excitatory/inhibitory (E/I) balance of neurotransmission in the mPFC, and these prefrontal cortical alterations may mediate behavioral changes. The impact of FKBP5 deficiency in synaptic transmission of the mPFC in normal or stressed conditions, however, remains uninvestigated. Therefore, in this study we investigated the differences of basal neuronal properties between WT and FKBP5 knock-out (KO) animals and the interaction between the absence of FKBP5 and GR activation in the mPFC.