Nada Zečević

Goldsmiths University of London

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N-Methyl D-Aspartate Receptor Antagonist Kynurenic Acid Affects Human Cortical Development

Frontiers in Neuroscience (2016)

Inseyah Bagasrawala Nada Zečević Nevena V. Radonjić

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation, acts as an endogenous N-methyl-D-aspartate receptor (NMDAR) antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and are considered to play a role in neurodevelopmental disorders. However, the consequences of KYNA-induced NMDAR blockade in human cortical development still remain elusive. To study the potential impact of KYNA on human neurodevelopment, we used an in vitro system of multipotent cortical progenitors, i.e., radial glia cells (RGCs), enriched from human cerebral cortex at mid-gestation (16-19 gestational weeks). KYNA treatment significantly decreased RGCs proliferation and survival by antagonizing NMDAR. This alteration resulted in a reduced number of cortical progenitors and neurons while number and activation of astrocytes increased. KYNA treatment reduced differentiation of RGCs into GABAergic neurons, while differentiation into glutamatergic neurons was relatively spared. Furthermore, in mixed cortical cultures KYNA triggered an inflammatory response as evidenced by increased levels of the pro-inflammatory cytokine IL-6. In conclusion, elevated levels of KYNA play a significant role in human RGC fate determination by antagonizing NMDARs and by activating an inflammatory response. The altered cell composition observed in cell culture following exposure to elevated KYNA levels suggests a mechanism for impairment of cortical circuitry formation in the fetal brain after viral infection, as seen in neurodevelopmental disorders such as schizophrenia.

Kynurenic acid

10.3389/fnins.2016.00435

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Citations (28)

Neurogenesis Continues in the Third Trimester of Pregnancy and Is Suppressed by Premature Birth

Journal of Neuroscience (2013)

Sabrina Malik Govindaiah Vinukonda Linnea R. Vose Daniel L. Diamond Bala B.R. Bhimavarapu

Premature infants exhibit neurodevelopmental delay and reduced growth of the cerebral cortex. However, the underlying mechanisms have remained elusive. Therefore, we hypothesized that neurogenesis in the ventricular and subventricular zones of the cerebral cortex would continue in the third trimester of pregnancy and that preterm birth would suppress neurogenesis. To test our hypotheses, we evaluated autopsy materials from human fetuses and preterm infants of 16–35 gestational weeks (gw). We noted that both cycling and noncycling Sox2 + radial glial cells and Tbr2 + intermediate progenitors were abundant in human preterm infants until 28 gw. However, their densities consistently decreased from 16 through 28 gw. To determine the effect of premature birth on neurogenesis, we used a rabbit model and compared preterm [embryonic day 29 (E29), 3 d old] and term (E32, <2 h old) pups at an equivalent postconceptional age. Glutamatergic neurogenesis was suppressed in preterm rabbits, as indicated by the reduced number of Tbr2 + intermediate progenitors and the increased number of Sox2 + radial glia. Additionally, hypoxia-inducible factor-1α, vascular endothelial growth factor, and erythropoietin were higher in term than preterm pups, reflecting the hypoxic intrauterine environment of just-born term pups. Proneural genes, including Pax6 and Neurogenin-1 and -2, were higher in preterm rabbit pups compared with term pups. Importantly, neurogenesis and associated factors were restored in preterm pups by treatment with dimethyloxallyl glycine, a hypoxia mimetic agent. Hence, glutamatergic neurogenesis continues in the premature infants, preterm birth suppresses neurogenesis, and hypoxia-mimetic agents might restore neurogenesis, enhance cortical growth, and improve neurodevelopmental outcome of premature infants.

PAX6

10.1523/jneurosci.4445-12.2013

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Citations (189)

Down-regulation of the axonal polysialic acid–neural cell adhesion molecule expression coincides with the onset of myelination in the human fetal forebrain

Neuroscience (2007)

Igor Jakovčevski Zhicheng Mo Nada Zečević

Polysialic acid

Forebrain

Subplate

10.1016/j.neuroscience.2007.07.044

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Citations (72)

Early oligodendrocyte progenitor cells in the human fetal telencephalon

Glia (2002)

Sonja Rakić Nada Zečević

Abstract Oligodendrocytes, the myelin‐producing cells in the central nervous system, represent a large portion of the total number of cells in the human brain. Using cell‐specific markers and antibodies to ventral homeodomain transcription factors, NKX2.1 and DLX2, we show here that a subpopulation of early oligodendrocyte progenitor cells (OPCs) in the human telencephalon may originate in the ganglionic eminence (GE). DLX2‐labeled OPCs form a well‐delineated stream of cells connecting the GE subventricular zone (SVZ) to the cortical intermediate zone through the anterior cortical SVZ. This population of cells is labeled by early OPCs markers, PDGFRα, Olig1, and NG2, and not with either neuronal, astrocyte, or late OPCs markers. Intriguingly, numerous CD68 + microglia/macrophages, nestin + neural stem cells, and CD34 + hematopoietic stem cells (HSCs) are also present in both the GE stream and the cortical SVZ. These cells could be colabeled with DLX2 as well as early OPCs markers. A separate subpopulation of early OPCs, present in the GE and cortical SVZ, did not express either DLX2 or CD68. These findings suggest that different subpopulations of early OPCs, characterized with different sets of transcription factors and cell‐specific markers, are present in human forebrain. These subpopulations may have different origins; one may originate in the cortical SVZ, while others may come from the GE and/or outside the CNS as hematopoietic stem cells. GLIA 41:117–127, 2003. © 2003 Wiley‐Liss, Inc.

OLIG2

Neuroepithelial cell

Ganglionic eminence

10.1002/glia.10140

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Citations (113)

Neuroprotective role of minocycline in co-cultures of human fetal neurons and microglia

Experimental Neurology (2008)

Radmila Filipovic Nada Zečević

Minocycline

10.1016/j.expneurol.2007.12.024

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Citations (44)

Developmental changes in human cerebellum: Expression of intracellular calcium receptors, calcium-binding proteins, and phosphorylated and nonphosphorylated neurofilament protein

The Journal of Comparative Neurology (1998)

Ana Milošević Nada Zečević

Few recent data are available on the development of the precise projection maps of the cerebellar cortex in humans. To address this topic, we studied temporal and spatial distribution of several antigens involved in calcium (Ca)-dependent processes: the intracellular Ca receptors, inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) and ryanodine receptor (RyR); the Ca-binding proteins, calbindin D-28k (CB), parvalbumin (PV), and synaptophysin; and phosphorylated (SMI 31) and nonphosphorylated (SMI 32) forms of neurofilament protein. All antigens were studied in the human cerebellum during intrauterine development. The results of this study show that immunocytochemical markers appeared in the following sequence: CB and both forms of neurofilament protein were observed at 4–5 gestational weeks (g.w.), PV appeared in the external granular layer and in a few Purkinje cells at 11 g.w., a diffuse immunostaining for IP3R1 and synaptophysin were observed at 13 g.w., whereas RyR was observed at 17–18 g.w. From 24 g.w. on, Purkinje cells expressed all four examined markers of intracellular Ca signaling as well as two forms of neurofilament protein. At the same time, compartmentation of the Purkinje cell layer was detected with three intracellular Ca-signaling molecules (IP3R1, CB, and PV) and with SMI 32. These results indicate that the developmentally regulated expression of antigens studied here may play a role in establishing a highly regular organization of terminal fields in the human cerebellar cortex. Moreover, the initial expression of these antigens is correlated temporally with other developmental processes in the cerebellum, such as cellular maturation, revealed by the immunoreaction to cytoskeletal protein, and synaptogenesis, revealed by immunoreaction to synaptophysin. J. Comp. Neurol. 396:442–460, 1998. © 1998 Wiley-Liss, Inc.

Neurofilament

Synaptophysin

Immunostaining

Calcium in biology

Calretinin

10.1002/(sici)1096-9861(19980713)396:4<442::aid-cne3>3.0.co;2-1

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Citations (45)

AP2γ regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex

Nature Neuroscience (2009)

Luísa Pinto Daniela Drechsel Marie-Theres Schmid Jovica Ninkovic Martin Irmler

Progenitor

Laminar organization

Corticogenesis

Neocortex

10.1038/nn.2399

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Citations (99)

Early appearance of tyrosine hydroxylase immunoreactivity in the retina of human embryos

Developmental Brain Research (1992)

Claudine Versaux‐Botteri Catherine Verney Nada Zečević Jeanine Nguyen‐Legros

10.1016/0165-3806(92)90169-w

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Citations (20)

Cortical progenitor cells in the developing human telencephalon

Glia (2005)

Brian M. Howard Yanhui Chen Nada Zečević

Abstract Radial glial (RG) cells have been demonstrated to be a major neural progenitor cell type, but in the human fetal brain, neither their molecular nor their spatiotemporal characteristics are well known. We used glial and neuronal‐specific antibodies to determine the antigen characteristics and distribution of RG cells and other neuronal progenitors in the human brain during the first half of intrauterine development. Proliferating RG (4A4 + ) cells in the ventricular zone (VZ) showed clear caudorostral and ventrodorsal gradients, spreading from the spinal cord to the ventral rhombencephalon, at embryonic stages (4.5–5.5 gestational weeks [gw]). However, in the same embryo, other dividing cells expressed the neuronal marker SMI‐31 and were present throughout the entire CNS, including the rostral prosencephalon. At the beginning of cortical neurogenesis (6 gw), proliferating VZ cells labeled either with neuronal markers (SMI‐31, MAP2, β‐III‐tubulin), double‐labeled 4A4 + /SMI‐31 + cells, or cells not labeled with these antibodies, were in close proximity to each other. At midgestation (17–24 gw), RG divisions were less frequent, but were spread throughout the entire cerebral cortex, including the subventricular and intermediate zones and the subpial granular layer. Several subtypes of RG were co‐labeled with vimentin and other glial markers (BLBP, GFAP, or GLAST) and quantified in vitro. In conclusion, the diversity of cortical progenitors in the human brain may, in part, explain the unique complexity of the human cerebral cortex. © 2005 Wiley‐Liss, Inc.

Human brain

Subplate

Progenitor

Fate mapping

10.1002/glia.20259

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Citations (83)

Rod, posjed i novakinje: samostan sv. Klare u Copertinu i integracija obitelji Kastrioti u talijanski jug (16.-18. stoljeće)

Zbornik Odsjeka za povijesne znanosti Zavoda za povijesne i društvene znanosti Hrvatske akademije znanosti i umjetnosti (2024)

Nada Zečević

U ovom se radu usredotočujem na odnose moći za koje se naslućuje da su se odvijali tijekom 16. i 17. stoljeća unutar zidina ženskog

10.21857/moxpjhzj4m

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