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Cereb Cortex. 2015 Sep;25(9):2683-95. doi: 10.1093/cercor/bhu066. Epub 2014 Apr 9.

Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia-Ischemia.

Author information

1
Department of Neurosurgery, Kirby Center for Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Abstract

Preterm birth impacts brain development and leads to chronic deficits including cognitive delay, behavioral problems, and epilepsy. Premature loss of the subplate, a transient subcortical layer that guides development of the cerebral cortex and axonal refinement, has been implicated in these neurological disorders. Subplate neurons influence postnatal upregulation of the potassium chloride co-transporter KCC2 and maturation of γ-amino-butyric acid A receptor (GABAAR) subunits. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) in Sprague-Dawley rats that mimic brain injury from extreme prematurity in humans would cause premature subplate loss and affect cortical layer IV development. Further, we predicted that the neuroprotective agent erythropoietin (EPO) could attenuate the injury. Prenatal TSHI induced subplate neuronal loss via apoptosis. TSHI impaired cortical layer IV postnatal upregulation of KCC2 and GABAAR subunits, and postnatal EPO treatment mitigated the loss (n ≥ 8). To specifically address how subplate loss affects cortical development, we used in vitro mechanical subplate ablation in slice cultures (n ≥ 3) and found EPO treatment attenuates KCC2 loss. Together, these results show that subplate loss contributes to impaired cerebral development, and EPO treatment diminishes the damage. Limitation of premature subplate loss and the resultant impaired cortical development may minimize cerebral deficits suffered by extremely preterm infants.

KEYWORDS:

GABA receptor; KCC2; development; prematurity; subplate; thalamocortical; white matter

PMID:
24722771
PMCID:
PMC4537428
DOI:
10.1093/cercor/bhu066
[Indexed for MEDLINE]
Free PMC Article

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