Neonatal Hyperoxia Perturbs Neuronal Development in the Cerebellum

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2017 May 27

PMID 28547531

Citations 25

Authors

Till Scheuer

Yuliya Sharkovska

Victor Tarabykin

Katharina Marggraf

Vivien Brockmoller

Christoph Buhrer

Stefanie Endesfelder

Thomas Schmitz

Affiliations

Soon will be listed here.

Abstract

Impaired postnatal brain development of preterm infants often results in neurological deficits. Besides pathologies of the forebrain, maldeveolopment of the cerebellum is increasingly recognized to contribute to psychomotor impairments of many former preterm infants. However, causes are poorly defined. We used a hyperoxia model to define neonatal damage in cerebellar granule cell precursors (GCPs) and in Purkinje cells (PCs) known to be essential for interaction with GCPs during development. We exposed newborn rats to 24 h 80% O from age P6 to P7 to identify postnatal and long-term damage in cerebellar GCPs at age P7 after hyperoxia and also after recovery in room air thereafter until P11 and P30. We determined proliferation and apoptosis of GCPs and immature neurons by immunohistochemistry, quantified neuronal damage by qPCR and Western blots for neuronal markers, and measured dendrite outgrowth of PCs by CALB1 immunostainings and by Sholl analysis of Golgi stainings. After hyperoxia, proliferation of PAX6+ GCPs was decreased at P7, while DCX + CASP3+ cells were increased at P11. Neuronal markers Pax6, Tbr2, and Prox1 were downregulated at P11 and P30. Neuronal damage was confirmed by reduced NeuN protein expression at P30. Sonic hedgehog (SHH) was significantly decreased at P7 and P11 after hyperoxia and coincided with lower CyclinD2 and Hes1 expression at P7. The granule cell injury was accompanied by hampered PC maturation with delayed dendrite formation and impaired branching. Neonatal injury induced by hyperoxia inhibits PC functioning and impairs granule cell development. As a conclusion, maldevelopment of the cerebellar neurons found in preterm infants could be caused by postnatal oxygen toxicity.

Citing Articles

Cerebellar Development and the Burden of Prematurity.

Muehlbacher T, Dudink J, Steggerda S Cerebellum. 2025; 24(2):39.

PMID: 39885037 PMC: 11782465. DOI: 10.1007/s12311-025-01790-6.

Mechanistic advances of hyperoxia-induced immature brain injury.

Song Y, Yang C Heliyon. 2024; 10(9):e30005.

PMID: 38694048 PMC: 11058899. DOI: 10.1016/j.heliyon.2024.e30005.

Targeting adenosine A receptors for early intervention of retinopathy of prematurity.

Chen X, Sun X, Ge Y, Zhou X, Chen J Purinergic Signal. 2024; .

PMID: 38329708 DOI: 10.1007/s11302-024-09986-x.

Apnea of prematurity induces short and long-term development-related transcriptional changes in the murine cerebellum.

Rodriguez-Duboc A, Basille-Dugay M, Debonne A, Riviere M, Vaudry D, Burel D Curr Res Neurobiol. 2023; 5:100113.

PMID: 38020806 PMC: 10663136. DOI: 10.1016/j.crneur.2023.100113.

Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat.

Puls R, Von Haefen C, Buhrer C, Endesfelder S Antioxidants (Basel). 2023; 12(4).

PMID: 37107355 PMC: 10136028. DOI: 10.3390/antiox12040980.

References

Stoodley C, Valera E, Schmahmann J . Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. Neuroimage. 2011; 59(2):1560-70. PMC: 3230671. DOI: 10.1016/j.neuroimage.2011.08.065. View

McDole B, Isgor C, Pare C, Guthrie K . BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo. Neuroscience. 2015; 304:146-60. PMC: 4547863. DOI: 10.1016/j.neuroscience.2015.07.056. View

Dammann O, Leviton A . Inflammatory brain damage in preterm newborns--dry numbers, wet lab, and causal inferences. Early Hum Dev. 2004; 79(1):1-15. DOI: 10.1016/j.earlhumdev.2004.04.009. View

Morrison M, Mason C . Granule neuron regulation of Purkinje cell development: striking a balance between neurotrophin and glutamate signaling. J Neurosci. 1998; 18(10):3563-73. PMC: 6793141. View

Hevner R, Hodge R, Daza R, Englund C . Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res. 2006; 55(3):223-33. DOI: 10.1016/j.neures.2006.03.004. View

Goldowitz D, Hamre K . The cells and molecules that make a cerebellum. Trends Neurosci. 1998; 21(9):375-82. DOI: 10.1016/s0166-2236(98)01313-7. View

Collin L, Doretto S, Malerba M, Ruat M, Borrelli E . Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development. Exp Cell Res. 2007; 313(13):2946-57. DOI: 10.1016/j.yexcr.2007.05.003. View

Kinney H . Human myelination and perinatal white matter disorders. J Neurol Sci. 2005; 228(2):190-2. DOI: 10.1016/j.jns.2004.10.006. View

Kapfhammer J . Cellular and molecular control of dendritic growth and development of cerebellar Purkinje cells. Prog Histochem Cytochem. 2004; 39(3):131-82. DOI: 10.1016/j.proghi.2004.07.002. View

10.

Volpe J . Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2008; 8(1):110-24. PMC: 2707149. DOI: 10.1016/S1474-4422(08)70294-1. View

11.

Sifringer M, Von Haefen C, Krain M, Paeschke N, Bendix I, Buhrer C . Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain. Oxid Med Cell Longev. 2015; 2015:530371. PMC: 4310240. DOI: 10.1155/2015/530371. View

12.

DAngelo E, Mazzarello P, Prestori F, Mapelli J, Solinas S, Lombardo P . The cerebellar network: from structure to function and dynamics. Brain Res Rev. 2010; 66(1-2):5-15. DOI: 10.1016/j.brainresrev.2010.10.002. View

13.

Harvey R, Napper R . Quantitative study of granule and Purkinje cells in the cerebellar cortex of the rat. J Comp Neurol. 1988; 274(2):151-7. DOI: 10.1002/cne.902740202. View

14.

Kaneko M, Yamaguchi K, Eiraku M, Sato M, Takata N, Kiyohara Y . Remodeling of monoplanar Purkinje cell dendrites during cerebellar circuit formation. PLoS One. 2011; 6(5):e20108. PMC: 3105010. DOI: 10.1371/journal.pone.0020108. View

15.

van Tilborg E, Heijnen C, Benders M, van Bel F, Fleiss B, Gressens P . Impaired oligodendrocyte maturation in preterm infants: Potential therapeutic targets. Prog Neurobiol. 2015; 136:28-49. DOI: 10.1016/j.pneurobio.2015.11.002. View

16.

Baud O, Gressens P . Hedgehog rushes to the rescue of the developing cerebellum. Sci Transl Med. 2011; 3(105):105ps40. DOI: 10.1126/scitranslmed.3003080. View

17.

Georgeson G, Szony B, Streitman K, Varga I, Kovacs A, Kovacs L . Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section. Eur J Obstet Gynecol Reprod Biol. 2002; 103(2):136-9. DOI: 10.1016/s0301-2115(02)00050-7. View

18.

Galeeva A, Treuter E, Tomarev S, Pelto-Huikko M . A prospero-related homeobox gene Prox-1 is expressed during postnatal brain development as well as in the adult rodent brain. Neuroscience. 2007; 146(2):604-16. DOI: 10.1016/j.neuroscience.2007.02.002. View

19.

Chang J, Leung M, Gokozan H, Gygli P, Catacutan F, Czeisler C . Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice. J Neuropathol Exp Neurol. 2015; 74(3):261-72. PMC: 4333719. DOI: 10.1097/NEN.0000000000000171. View

20.

Bellamy T . Interactions between Purkinje neurones and Bergmann glia. Cerebellum. 2006; 5(2):116-26. DOI: 10.1080/14734220600724569. View