Development of microglia in the cerebral white matter of the human fetus and infant

Abstract

Although microglial activation may be an initial beneficial response to a variety of insults, prolonged activation can release toxic substances and lead to cell death. Microglial activation secondary to hypoxia-ischemia and/or infection in immature cerebral white matter is important in the pathogenesis of periventricular leukomalacia (PVL), the major pathological substrate of cerebral palsy in the premature infant. We hypothesize that a transient overexpression in activated microglial density occurs normally in the cerebral white matter of the human fetus during the peak window of vulnerability for PVL. Such an increase could render this region susceptible to insults that cause prolonged microglial activation, as conceptualized in PVL. To examine the developmental profile of microglia in the human fetus and infant brain, immunocytochemistry with microglial specific markers were used in 23 control (non-PVL) cases ranging from 20 to 183 postconceptional (PC) weeks. Tomato lectin, used to identify microglial morphology, revealed that the cerebral white matter of the human fetus and infant is densely populated with intermediate and amoeboid microglia; the latter is indicative of an activated state. Quantitative analysis with CD68 showed increased density of activated microglia in the cerebral white matter of the fetus (<37 PC weeks) relative to the neonate/infant (> or =37 PC weeks) and to the overlying cortex of either age group (P = 0.01). The primary finding of a transient, developmental-dependent overabundance of CD68-activated microglia in the cerebral white matter of the fetus suggests a potential "priming" of this area for diverse brain insults characterized by activation of microglia, particularly PVL. J.

Microglia activation in the extremely preterm human brain

“…The large numbers of microglia in the control PVWM as compared with other areas is consistent with previous studies (14,25,26), in which they were also mainly of amoeboid or intermediate active morphology. Microglia in the preterm PVWM were predominantly Iba1/CD68-immunopositive activated microglia.…”

“…It was proposed that the normal developmental increase in resident microglia renders the human neonatal periventricular white matter (PVWM) more susceptible to injury (6,8,14,15). The PVWM regions are the most frequent site of preterm white matter injuries, such as periventricular leukomalacia, punctate lesions, and diffuse excessive high signal intensity, which are evident on magnetic resonance imaging (MRI).…”

Microglia Proliferation Is Controlled by P2X7 Receptors in a Pannexin-1-Independent Manner during Early Embryonic Spinal Cord Invasion

“…Microglia are the resident immune cells of the CNS, which begin to colonize at early embryonic developmental stages (MarinTeva et al, 1998;Dalmau et al, 2003;Billiards et al, 2006;Rigato et al, 2011). In the mouse embryo, the colonization of the spinal cord (SC) by microglia involves several processes, including microglia proliferation at the periphery of the parenchyma (Rigato et al, 2011).…”

A New Rabbit Model of Pediatric Traumatic Brain Injury

“…14,15 In humans, myelination of sensory and motor fibers starts at birth and continues during the first year of life, 34,35 with persistence of microglia in the white matter tracts up to two years of age, which corresponds to the period of peak myelination. 36 Therefore, the microglial response seen after injury in relation to development would mimic that seen in humans.…”

“…They decrease in density in the postnatal period but they remain in the white matter tracts up to two years of age and eventually migrating to the cortex by adulthood. 36 During development, activated microglia render a supportive role in myelinogenesis and axonogenesis by stimulating synthesis of myelin basic protein and the induction of laminin, an extracellular matrix molecule that enhances neurite outgrowth. 36,55 Microglia can exist in two activation states, M1 (classical activation, or pro-inflammatory state) and M2 (alternative activation, or anti-inflammatory form responsible for clearance of debris, repair, and regeneration).…”