Loss of FKBP5 Affects Neuron Synaptic Plasticity: An Electrophysiology Insight

Abstract

FKBP5 (FKBP51) is a glucocorticoid receptor (GR) binding protein, which acts as a co-chaperone of heat shock protein 90 (HSP90) and negatively regulates GR. Its association with mental disorders has been identified, but its function in disease development is largely unknown. Long-term potentiation (LTP) is a functional measurement of neuronal connection and communication, and is considered one of the major cellular mechanisms that underlies learning and memory, and is disrupted in many mental diseases. In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. The frequency of mEPSCs was decreased in KO hippocampus, indicating a decrease in excitatory synaptic activity. While no differences were found in levels of glutamate between KO and WT, a reduction was observed in the expression of excitatory glutamate receptors (NMDAR1, NMDAR2B and AMPAR), which initiate and maintain LTP. The expression of the inhibitory neurotransmitter GABA was found to be enhanced in Fkbp5 KO hippocampus. Further investigation suggested that increased expression of GAD65, but not GAD67, accounted for this increase. Additionally, a functional GABAergic alteration was observed in the form of increased mIPSC frequency in the KO hippocampus, indicating an increase in presynaptic GABA release. Our findings uncover a novel role for Fkbp5 in neuronal synaptic plasticity and highlight the value of Fkbp5 KO as a model for studying its role in neurological function and disease development.

FKBP51 Modulates Hippocampal Size and Function in Post-translational Regulation of Parkin

“…Greater dendrite outgrowth in the Fkbp51 KO could alter normal neuronal function, resulting in connectivity differences. Our group and others recently found Fkbp51 plays a role in synaptic plasticity (Blair et al, 2019;Qiu et al, 2019). The neuronal polarization is a dynamic process including microtubule protein transportation, cross-linking between microtubules and other proteins, as well as the internal traction force in the axon (Courchet et al, 2013;Wilson and Gonzalez-Billault, 2015;Xu et al, 2013;Yadaw et al, 2019).…”

Associations of psychiatric disease and aging onFKBP5expression converge on cortical supragranular neurons

“…The alteration of FKBP5 expression in excitatory neurons is of functional importance, given that knock-out of Fkbp5 in mice has been shown to decrease long-term potentiation and increase presynaptic GABA release (Qiu et al, 2019). Transgenic mice overexpressing the human FKBP51 display impaired long-term depression as well as spatial reversal learning and memory.…”

Building Resilience with Aerobic Exercise: Role of FKBP5

“…Likewise, the antidepressant effect of paroxetine was related to an enhancement of both BDNF and FKBP5 [19]. Nevertheless, although the mechanism by which FKBP5 is able to modulate mBDNF levels is still unknown, it has been proposed that its interaction with NMDA receptors, as well as with inhibitory synapses in brain regions such as the hippocampus could affect the neuronal activity and consequently BDNF levels [27,28].…”