White matter astrocytes in health and disease

Abstract

Myelination by oligodendrocytes is a highly specialized process that relies on intimate interactions between the axon and the oligodendrocytes. Astrocytes have an important part in facilitating myelination in the CNS, however, comparatively less is known about how they affect myelination. This review therefore summarizes the literature and explores lingering questions surrounding differences between white matter and gray matter astrocytes, how astrocytes support myelination, how their dysfunction in pathological states contributes to myelin pathologies and how astrocytes may facilitate remyelination. We discuss how astrocytes in the white matter are specialized to promote myelination and myelin maintenance by clearance of extracellular ions and neurotransmitters and by secretion of pro-myelinating factors. Additionally, astrocyte-oligodendrocyte coupling via gap junctions is crucial for both myelin formation and maintenance, due to K(+) buffering and possibly metabolic support for oligodendrocytes via the panglial syncytium. Dysfunctional astrocytes aberrantly affect oligodendrocytes, as exemplified by a number of leukodystrophies in which astrocytic pathology is known as the direct cause of myelin pathology. Conversely, in primary demyelinating diseases, such as multiple sclerosis, astrocytes may facilitate remyelination. We suggest that specific manipulation of astrocytes could help prevent myelin pathologies and successfully restore myelin sheaths after demyelination.

Keywords: astrocyte heterogeneity; astrocytes; myelination; oligodendrocytes; white matter pathology.

Figure 1

3D reconstruction of astrocytes stained for GFAP. Fibrous astrocyte in mouse corpus callosum (top left) and in human subcortical white matter (bottom left). Protoplasmic astrocyte in mouse cortex (top right) and human cortex (bottom right).

Figure 2

A: Astrocytes in the hippocampus of wild type mouse express GFAP (green) and GLT-1 (red). B: Astrocytes in the hippocampus of Alexander Disease model GFAP-R23H mouse have hypertrophic GFAP-positive processes (green) and express low levels of GLT-1 (red); from Tian et al., Neuropathol Exp Neurol (2010). C: Hematoxylin and eosin stain stain of periventricular white matter showing Rosenthal fibers (arrows) in Alexander Disease model R76H/+ mouse; from Hagemann et al., J Neurosci (2006). D: Electron micrograph of post-mortem tissue from a 17 month old child with Alexander Disease showing an astrocyte with Rosenthal fibers (arrows) in the cytoplasm next to the nucleus (N); from Eng et al., J Neurosci Res (1998).