The spatiotemporal dynamics of microglia across the human lifespan.

Microglia, the brain's resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in knowledge by establishing an extensive collection of 97 post-mortem tissues in order to enable quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing waves in microglial density across gestation, infancy, and childhood, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNA-seq and single-cell RNA-seq datasets. This study provides a detailed insight into the spatiotemporal dynamics of microglia across the human lifespan and serves as a foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development.

Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.

The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia.

The human fetal cerebral cortex develops through a series of partially overlapping histogenetic events which occur in transient cellular compartments, such as the subplate zone. The subplate serves as waiting compartment for cortical afferent fibers, the major site of early synaptogenesis and neuronal differentiation and the hub of the transient fetal cortical circuitry. Thus, the subplate has an important but hitherto neglected role in the human fetal cortical connectome. The subplate is also an important compartment for radial and tangential migration of future cortical neurons. We review the diversity of subplate neuronal phenotypes and their involvement in cortical circuitry and discuss the complexity of late neuronal migration through the subplate as well as its potential relevance for pathogenesis of migration disorders and cortical dysplasia. While migratory neurons may become misplaced within the subplate, they can easily survive by being involved in early subplate circuitry; this can enhance their subsequent survival even if they have immature or abnormal physiological activity and misrouted connections and thus survive into adulthood. Thus, better understanding of subplate developmental history and various subsets of its neurons may help to elucidate certain types of neuronal disorders, including those accompanied by epilepsy.

Neural ECM in laminar organization and connectivity development in healthy and diseased human brain.

The neural extracellular matrix (ECM) provides a supportive framework for differentiating cells and their processes and regulates morphogenetic events by spatially and temporally relevant localization of signaling molecules and by direct signaling via receptor and/or coreceptor-mediated action. The embryonic human brain and fetal human brain contain large amounts and a diversity of extracellular matrix components, which are especially prominent in the transient subplate zone, in the crossroads of axonal pathways, at the developing cortical-white matter interface, and in the marginal zone. Perinatal and postnatal reorganizations of these tissue compartments extend into the second year of life. Developmental changes in the amount and composition of the extracellular matrix (as well as changes in fiber architectonics) are significant for plastic responses to damage and for changes in magnetic resonance imaging (MRI) signal intensity of the fetal and early postnatal human brain. In this chapter, we discuss the expression pattern of the major components of the fetal ECM of the human brain and the role they play during laminar and connectivity development in healthy brain and in the neurodevelopmental disorders. The aim of the chapter is to elucidate ECM-related developmental events as potential models of successful functional recovery after injury and to explore its relevance for diagnostic and therapeutic approaches.

Involvement of the subplate zone in preterm infants with periventricular white matter injury.

Studies of periventricular white matter injury (PWMI) in preterm infants suggest the involvement of the transient cortical subplate zone. We studied the cortical wall of noncystic and cystic PWMI cases and controls. Non-cystic PWMI corresponded to diffuse white matter lesions, the predominant injury currently detected by imaging. Glial cell populations were analyzed in post-mortem human frontal lobes from very preterm [24­29 postconceptional weeks (pcw)] and preterm infants (30­34 pcw) using immunohistochemistry for glial fibrillary acidic protein (GFAP), monocarboxylate transporter 1(MCT1), ionized calcium-binding adapter molecule 1 (Iba1), CD68 and oligodendrocyte lineage (Olig2). Glial activation extended into the subplate in non-cystic PWMI but was restricted to the white matter in cystic PWMI. Two major age-related and laminar differences were observed in non-cystic PWMI: in very preterm cases, activated microglial cells were increased and extended into the subplate adjacent to the lesion, whereas in preterm cases, an astroglial reaction was seen not only in the subplate but throughout the cortical plate. There were no differences in Olig2-positive pre-oligodendrocytes in the subplate inPWMI cases compared with controls. The involvement of gliosis in the deep subplate supports the concept of the complex cellular vulnerability of the subplate zone during the preterm period and may explain widespread changes in magnetic resonance signal intensity in early PWMI.

Pineal cysts - a benign consequence of mild hypoxia in a near-term brain?

BACKGROUND: Pineal cysts are benign glial uniloculated or multiloculated fluid-filled sacs located in the pineal gland region. Small pineal cysts are often found incidentally in healthy adults in 1.5-10.8%. Large cysts may cause neurological problems due to pressure exertion on adjacent structures. METHODS: We have used prospective, observational study of an inception cohort of 16 adolescents of mean age 21.69 years (SD=±0.87) with mild (68.7%) to moderate (31.3%) HIE: 7 girls (43.8%) and 9 (56.3%) boys, born with mean gestational age of 35.75 weeks (SD=±3.80) and mean birthweight of 2 644 g (SD=±815). HIE was confirmed by presence of abnormal CTG and/or meconium and/or Apgar scores less than 7 at 5 minutes and/or need for resuscitation and/or cord pH less than 7.2 and /or BE more than -15. The clinical assessment of HIE was done according to the Sarnat-Sarnat scoring. Neonatal data, including EEG and imaging data, were collected. Adolescents were scanned with 3T Magnetom Trio Tim, Siemens, head coil 12 channels, regular sequences and sagittal 3D magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence with voxel size 1 mm3. Neurological outcome was determined. RESULTS: In 1 patient we found cortical dysplasia and 1 had a panic attack hence their data were omitted. In the group of 14 we have incidentally found in 5 patients a larger, asymptomatic pineal cysts with the overall incidence of 36%. Other MR findings in the group were in 50% white matter injury, in 50% thinner corpus callosum. No statistically significant difference between neonatal cUS and late follow-up MRI (p=0.881) was found. Correlation was not significant with Spearman correlation coefficient 0.201. Presence of pineal cysts was linked to thinner corpus callosum (p=0.005). CONCLUSIONS: We propose that larger pineal cyst, in the absence of other imaging findings except for thinner corpus callosum, is a benign consequence of mild hypoxia in a near-term brain. Our findings warrant a larger study.

Prolonged coexistence of transient and permanent circuitry elements in the developing cerebral cortex of fetuses and preterm infants.

The aim of this paper is to evaluate correlative magnetic resonance imaging (MRI) and histological parameters of development of cortical afferents during pathfinding and target selection in transient fetal cerebral laminas in human fetuses and preterm infants. The transient fetal subplate zone, situated between the fetal white matter (i.e. intermediate zone) and the cortical plate, is the crucial laminar compartment for development of thalamocortical and corticocortical afferents. The prolonged coexistence of transient (endogenously active) and permanent (sensory-driven) circuitry within the transient fetal zones is a salient feature of the fetal and preterm cortex; this transient circuitry is the substrate of cerebral functions in preterm infants. Another transient aspect of organization of developing fibre pathways is the abundance of extracellular matrix and guidance molecules in periventricular crossroads of projection and corticocortical pathways. Both the subplate zone and periventricular crossroads are visible on MRI in vivo and in vitro. Hypoxic-ischaemic lesions of periventricular crossroads are the substrate for motor, sensory, and cognitive deficits after focal periventricular leukomalacia (PVL). Lesions of distal portions of the white matter and the subplate zone are the substrate for diffuse PVL. The neuronal elements in transient fetal zones form a developmental potential for plasticity after perinatal cerebral lesions.