Expression of EAAT2 in neurons and protoplasmic astrocytes during human cortical development.

The major regulators of synaptic glutamate in the cerebral cortex are the excitatory amino acid transporters 1-3 (EAAT1-3). In this study, we determined the cellular and temporal expression of EAAT1-3 in the developing human cerebral cortex. We applied single- and double-label immunocytochemistry to normative frontal or parietal (associative) cortex samples from 14 cases ranging in age from 23 gestational weeks to 2.

Brainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome.

Impaired brainstem responses to homeostatic challenges during sleep may result in the sudden infant death syndrome (SIDS). Previously we reported a deficiency of serotonin (5-HT) and its key biosynthetic enzyme, tryptophan hydroxylase (TPH2), in SIDS infants in the medullary 5-HT system that modulates homeostatic responses during sleep. Yet, the underlying basis of the TPH2 and 5-HT deficiency is unknown.

Late development of the GABAergic system in the human cerebral cortex and white matter.

Despite the key role of γ-aminobutyric acid (GABA) neurons in the modulation of cerebral cortical output, little is known about their development in the human cortex. We analyzed several GABAergic parameters in standardized regions of the cerebral cortex and white matter in a total of 38 human fetuses and infants from 19 gestational weeks to 2.7 postnatal years using immunocytochemistry, Western blotting, tissue autoradiography, and computer-based cellular quantitation.

Brainstem serotonergic deficiency in sudden infant death syndrome.

Context: Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS.

Objective: To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase [TPH2]), or both.

Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin.

Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [beta-amyloid precursor protein (beta-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis.

Glutamate transporter EAAT2 expression is up-regulated in reactive astrocytes in human periventricular leukomalacia.

The major neuropathological correlate of cerebral palsy in premature infants is periventricular leukomalacia (PVL), a disorder of the immature cerebral white matter. Cerebral ischemia leading to excitotoxicity is thought to be important in the pathogenesis of this disorder, implying a critical role for glutamate transporters, the major determinants of extracellular glutamate concentration. Previously, we found that EAAT2 expression is limited primarily to premyelinating oligodendrocytes early in development and is rarely observed in astrocytes until >40 weeks.

Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia.

The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2.

The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter.

The major brain abnormality underlying cerebral palsy in premature infants is periventricular leukomalacia (PVL), a lesion of the immature cerebral white matter. Oligodendrocyte precursors (pre-OLs; O4(+)O1(-)) predominate in human cerebral white matter during the peak time frame for PVL (24-32 gestational weeks) and are vulnerable to excitotoxicity. We hypothesize that PVL reflects, in part, excitotoxicity to pre-OLs resulting from cerebral ischemia/reperfusion.

Axonal development in the cerebral white matter of the human fetus and infant.

After completion of neuronal migration to form the cerebral cortex, axons undergo rapid elongation to their intra- and subcortical targets, from midgestation through infancy. We define axonal development in the human parietal white matter in this critical period. Immunocytochemistry and Western blot analysis were performed on 46 normative cases from 20-183 postconceptional (PC) weeks.

Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter.

Periventricular leukomalacia (PVL) involves free radical injury to developing oligodendrocytes (OLs), resulting from ischemia/reperfusion, particularly between 24 and 32 gestational weeks. Using immunocytochemistry and Western blots, we tested the hypothesis that this vulnerability to free radical toxicity results, in part, from developmental lack of superoxide dismutases (SOD)-1 and -2, catalase, and glutathione peroxidase (GPx) in the telencephalic white matter of the human fetus. During the period of greatest PVL risk and through term (> or = 37 weeks), expression of both SODs (for conversion of O2- to H2O2) significantly lagged behind that of catalase and GPx (for breakdown of H2O2), which, in contrast, superseded adult levels by 30 gestational weeks.

Arrested oligodendrocyte lineage progression during human cerebral white matter development: dissociation between the timing of progenitor differentiation and myelinogenesis.

Immature oligodendrocytes (OLs) derive from a large pool of late OL progenitors that populate human cerebral white matter throughout the latter half of gestation. We recently reported that a minor population of immature OLs are present in human cerebral white matter for at least 3 months before these cells commit to myelinogenesis around 30 wk postconceptional age. Since this finding supports dissociation between the events that regulate human immature OL maturation and their commitment to myelinogenesis, we characterized here the cellular sequence of events that characterize immature OLs during the transition from a premyelinating to a myelinating state.