Mild myelin disruption elicits early alteration in behavior and proliferation in the subventricular zone.

Elizabeth A Gould,Anan Li,Douglas Shepherd,Nicolas Busquet,Nicholas M George,Fabio M Simoes de Souza,Diego Restrepo,Robert M Dietz,Paco S Herson,Wendy B Macklin

doi:10.7554/elife.34783

Abstract

Myelin, the insulating sheath around axons, supports axon function. An important question is the impact of mild myelin disruption. In the absence of the myelin protein proteolipid protein (PLP1), myelin is generated but with age, axonal function/maintenance is disrupted. Axon disruption occurs in Plp1-null mice as early as 2 months in cortical projection neurons. High-volume cellular quantification techniques revealed a region-specific increase in oligodendrocyte density in the olfactory bulb and rostral corpus callosum that increased during adulthood. A distinct proliferative response of progenitor cells was observed in the subventricular zone (SVZ), while the number and proliferation of parenchymal oligodendrocyte progenitor cells was unchanged. This SVZ proliferative response occurred prior to evidence of axonal disruption. Thus, a novel SVZ response contributes to the region-specific increase in oligodendrocytes in Plp1-null mice. Young adult Plp1-null mice exhibited subtle but substantial behavioral alterations, indicative of an early impact of mild myelin disruption.

Highlights

Myelin-producing cells of the central nervous system, oligodendrocytes, facilitate normal neuronal function
Plp1-eGFP+ cell bodies and processes were visible in the cleared tissue (Figure 1C,D), and a comprehensive survey of changes in Plp1-eGFP+ cell number by cleared tissue digital scanned lightsheet microscopy (C-DSLM)(Ryan et al, 2017) suggested an increase in Plp1-eGFP+ oligodendroocytes in 6M Plp1-null olfactory bulb (OB) and a significant increase in oligodendrocytes in the forebrain (Figure 1E, Table 1)
Using the same quantification method, the oligodendrocyte density increase was confirmed with the pan oligodendrocyte marker, Olig2, and an increase in Olig2+cells was observed in the rostral corpus callosum (CC) prior to increased Plp1-eGFP+ cells (Figure 1I,J)

Summary

Introduction

Myelin-producing cells of the central nervous system, oligodendrocytes, facilitate normal neuronal function. While myelin acts as an insulator, it has additional roles crucial for axonal activity. Myelin disruption contributes to a growing list of neurological diseases, including the most common neurological disease in young adults, multiple sclerosis (MS)(Browne et al, 2014). Patients with extensive demyelination, such as in MS, exhibit severe motor deficits, as well as psychiatric symptoms, including a higher incidence of cognitive dysfunction (Feinstein et al, 2013). While psychiatric diseases are not typically associated with overt demyelination, subtle white matter abnormalities have been

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