Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity

Int J Mol Sci. 2020 Dec 28;22(1):211. doi: 10.3390/ijms22010211.

Abstract

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.

Keywords: encephalopathy of prematurity; insulin-like growth factor I; interneurons; mesenchymal stem cells; neurodevelopmental disorders; preterm birth; regenerative medicine.

MeSH terms

  • Administration, Intranasal
  • Animals
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / pathology
  • Disease Models, Animal
  • Female
  • GABAergic Neurons
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Hypoxia-Ischemia, Brain / pathology
  • Hypoxia-Ischemia, Brain / therapy*
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / therapeutic use*
  • Interneurons*
  • Mesenchymal Stem Cell Transplantation*
  • Mice, Inbred C57BL
  • Pregnancy
  • Rats, Wistar
  • Social Behavior

Substances

  • Insulin-Like Growth Factor I