Glucocorticoid receptor knockout in mouse Schwann Cell is associated with decreased motor performances and nerve morphological abnormalities

Glucocorticoid hormones (GC) are major regulators of stress, metabolism, and immunity. Glucocorticoid compounds are frequently used in medicine due to their effective actions as immunomodulators, but they can also present devastating side effects. GC bind to two corticosteroid receptors mediating their effects: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Despite extensive studies on the role of these receptors in most tissues and organs very little data is available on their role in the peripheral nervous system (PNS). Schwann cells (SC) are the main glial cells of the PNS. They are responsible for myelination and present a trophic role for axons. We previously knocked out the MR specifically in SC and found an increase in GR abundance in the sciatic nerve associated with an increase in myelin sheath thickness of large fibers. In this work, GR was also knocked-out in the sciatic nerve, generating the SCGRKO mouse model. Both males and females SCGRKO mice showed reduced performance in grip strength test starting from 6 months of age and in the flat ladder Locotronic® test starting from 3 months. Electron microscopy of sciatic nerve sections from these animals at one year revealed the frequent presence of abnormal swelling of the myelin sheath in SCGRKO associated with a general increase in myelin sheath thickness. Gene expression analysis in young adult (two-month-old) sciatic nerves pointed to a reduction of glucocorticoid signaling genes. In conclusion, this work showed for the first time an unambiguous role of Schwann Cell GR in peripheral nerve integrity with potential implications in public health.