Myelination defects in the medial prefrontal cortex of Fkbp5 knockout mice

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis plays a principal role in stress response regulation and has been implicated in the etiology of stress-related disorders. The HPA axis regulates the normal synthesis and release of glucocorticoids; dysregulation of the HPA axis causes abnormal responses to stress. FK506-binding protein 5 (FKBP5), a co-chaperone of heat shock protein 90 in the glucocorticoid receptor (GR) molecular complex, is a key GR sensitivity regulator. FKBP5 single nucleotide polymorphisms are associated with dysregulated HPA axis and increased risk of stress-related disorders, including posttraumatic stress disorder (PTSD) and depression. In this study, we profiled the microRNAs (miRNAs) in the medial prefrontal cortex of Fkbp5 knockout (Fkbp5^-/- ) mice and identified the target genes of differentially expressed miRNAs using sequence-based miRNA target prediction. Gene ontology analysis revealed that the differentially expressed miRNAs were involved in nervous system development, regulation of cell migration, and intracellular signal transduction. The validation of the expression of predicted target genes using quantitative polymerase chain reaction revealed that the expression of axon development-related genes, specifically actin-binding LIM protein 1 (Ablim1), lemur tyrosine kinase 2 (Lmtk2), kinesin family member 5c (Kif5c), neurofascin (Nfasc), and ephrin type-A receptor 4 (Epha4), was significantly decreased, while that of brain-derived neurotrophic factor (Bdnf) was significantly increased in the brain of Fkbp5^-/- mice. These results suggest that axonal development-related genes can serve as potential targets in future studies focused on understanding the pathophysiology of PTSD.

Keywords: Nfasc; PTSD; small RNA-seq; target prediction.