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Mol Cell Neurosci. 2014 Jul;61:152-62. doi: 10.1016/j.mcn.2014.06.009. Epub 2014 Jun 28.

Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury.

Author information

1
Department of Neurology, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA.
2
Department of Pediatrics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
3
Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
4
Department of Neurology, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital & Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA. Electronic address: Shenandoah.Robinson@childrens.harvard.edu.

Abstract

Therapeutic agents that restore the inhibitory actions of γ-amino butyric acid (GABA) by modulating intracellular chloride concentrations will provide novel avenues to treat stroke, chronic pain, epilepsy, autism, and neurodegenerative and cognitive disorders. During development, upregulation of the potassium-chloride co-transporter KCC2, and the resultant switch from excitatory to inhibitory responses to GABA guide the formation of essential inhibitory circuits. Importantly, maturation of inhibitory mechanisms is also central to the development of excitatory circuits and proper balance between excitatory and inhibitory networks in the developing brain. Loss of KCC2 expression occurs in postmortem samples from human preterm infant brains with white matter lesions. Here we show that late gestation brain injury in a rat model of extreme prematurity impairs the developmental upregulation of potassium chloride co-transporters during a critical postnatal period of circuit maturation in CA3 hippocampus by inducing a sustained loss of oligomeric KCC2 via a calpain-dependent mechanism. Further, administration of erythropoietin (EPO) in a clinically relevant postnatal dosing regimen following the prenatal injury protects the developing brain by reducing calpain activity, restoring oligomeric KCC2 expression and attenuating KCC2 fragmentation, thus providing the first report of a safe therapy to address deficits in KCC2 expression. Together, these data indicate it is possible to reverse abnormalities in KCC2 expression during the postnatal period, and potentially reverse deficits in inhibitory circuit formation central to cognitive impairment and epileptogenesis.

KEYWORDS:

Calpain; Erythropoietin; Hypoxia–ischemia; KCC2; Perinatal brain injury

PMID:
24983520
PMCID:
PMC4134983
DOI:
10.1016/j.mcn.2014.06.009
[Indexed for MEDLINE]
Free PMC Article

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