184 Chapter 8 Table 1. Microglia differences in white and grey matter White matter Grey matter Ref Healthy conditions Microglial density High Low 5,51 Biomechanical properties (viscoelasticity) High, decreased in inflammation and after uptake in of myelin Low, increased in inflammation, decreased after myelin intake 59 Nf-κB pathway expression Enriched 58 Type-1 interferon pathway expression Enriched during remyelination Enriched 58,62, 67,68 Marker expression for Antigen presentation, phagocytosis and cholesterol transport High Low 69,70 TREM2-dependent white matter associated microglia (WAMs) Present Absent 71 Expression of Sall1 (loss of Sall1 results in inflammation) Enriched 72 Disease / Ageing SPP1 expression in ageing Enriched 69 Lipid metabolism in MS High Low 58 Glycolysis and iron homeostasis in MS Low High 58 Expression of Sall1 Reduced Enriched 72 Microgliosis after cuprizone administration Severe Mild 73 microglial gene expression during development. By sequencing the whole brain, Hammond et al.62 and Li et al.46 found that postnatal microglia (postnatal day (P) 4/5 and P7 respectively) display marked transcriptomic heterogeneity in contrast to adult microglia. Of particular interest, both studies identified amicroglial state associated with the developing whitematter, sometimes referred to as the proliferative-region-associated microglia (PAM) state. While the role of this developmental white matter microglial state is not fully understood, it appears to represent highly phagocytic cells as ∼13% of Clec7a+ microglia contain Mbp transcripts, and CLEC7A+ microglia in the corpus callosum and cerebellum phagocytose beads and nuclei46. While CX3CR1-eGFP+ microglia phagocytose apoptotic oligodendrocytes (cleaved caspase-3+ MBP+) in the developing white matter46 whether these represent the CLEC7A+ state remains to be determined. Although these studies have identified a white matter-associated microglia state by sequencing the whole brain, the heterogeneity of microglia specifically in the white matter during development has yet to be resolved. These studies complement previous work identifying a microglia state associated with developingwhitematter identifiedbyexpressionofCD11c (Itgax)64,74,whichappears transiently in the corpus callosum and cerebellar white matter of mice during the early postnatal period74. Not all microglia in the white matter express CD11c, indicating heterogeneity within white matter during development. CD11c-driven knockout of the gene encoding the growth factor insulin-like growth factor (IGF)-1 causes a reduction in myelinated axons and alters myelin thickness, suggesting a role of CD11c+ cells in regulating developmental myelination74. Whether the CD11c+ and CLEC7A+ microglia represent the same or distinct states within the
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