Elucidating the role of perineurial glia in peripheral debris clearance in zebrafish larvae (Danio rerio)

Abstract

The peripheral nervous system (PNS) is the division of the nervous system that consists of all nerves lying outside of the brain and spine (central nervous system (CNS)). Primarily, the role of the PNS is to bridge the gap between the CNS and the environment. The PNS fulfills this role by carrying motor and sensory information to and from the CNS via the somatic nervous system and regulates involuntary physiological functions through the autonomic nervous system. When the PNS’ ability to carry information is disrupted via injury, the body’s capability to regulate these functions becomes diminished and pathological issues begin to surface. The component functioning as the blood-nerve barrier for peripheral nerves, the perineurium, has emerged as an important influencer in the degenerative process following nerve injury. Recent work in zebrafish (Danio rerio) has revealed that perineurial glia are the first to bridge injury gaps following nerve transection, and that perineurial glia extend processes into the injury site and phagocytize neuronal debris. While this work elucidated how perineurial glia respond to an acute injury induced by laser transection, how the perineurium behaves when subject to clinically relevant neurodegeneration remains a mystery. Here we use an established model of hyperglycemia-induced neurodegeneration in conjunction with in vivo imaging in transgenic zebrafish to visualize the dynamics of the perineurial glia during neurodegeneration. We demonstrate that hyperglycemia induces lysosomal activity in perineurial glia and that they phagocytize axonal, Schwann cell, and potentially oligodendrocyte debris by extending processes to the debris. We present that hyperglycemia also induces migration of olig2+ cells out of the spinal cord which then are seen associating with motor nerves potentially attempting to remyelinate them following demyelination caused by hyperglycemia. Finally, we uncover a phenomenon of cells and/or debris being ejected from the spinal cord nerve roots at regular intervals prior to death in these zebrafish. This may indicate a failure of a population of glia at motor exit points or further migration of oligodendrocytes. Collectively, these data provide insight into how the perineurial glia and other nerve components respond to peripheral neurodegeneration and reveal a previously unknown moribund process.