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

Josine E G Vaes,Rik Van Vliet,Myrna J V Brandt,Cora H Nijboer,Manon J N L Benders,Chantal M Kosmeijer,Marthe Kaal

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.

Highlights

Preterm birth is a major cause of neonatal brain injury, leading to significant neurodevelopmental morbidity [1,2,3,4]
To study the total number of GABAergic interneurons in rats subjected to fetal inflammation and postnatal hypoxia (FIPH), brains sections were stained for the general interneuron marker GAD67, an enzyme essential for GABA synthesis
At P15, a significant increase in the number of interneurons per mm2 in both the upper (I-IV) and lower (V-VI) cortical layers of both hemispheres was observed in FIPH rats compared to controls (p = 0.014 and p = 0.003, respectively) (Figure 1A–C)

Summary

Introduction

Preterm birth is a major cause of neonatal brain injury, leading to significant neurodevelopmental morbidity [1,2,3,4]. Preclinical and clinical imaging studies have identified distinct patterns of white and (subtle) gray matter deficits in pretermborn neonates, collectively known as Encephalopathy of Prematurity (EoP). These deficits are believed to originate from impaired brain development with peri- and postnatal insults interfering with a multitude of developmental processes that occur in the third trimester of pregnancy [5,6,7]. Disturbances in the number and function of interneurons have been frequently proposed in the underlying pathophysiology of neurodevelopmental disorders, such as attention deficit disorder (ADD), autism spectrum disorder (ASD), and mood disorders These are neurodevelopmental disorders highly prevalent in the preterm population [14,17,18]. Impairments in interneuron development could play a significant role in EoP pathophysiology and associated neurodevelopmental outcome

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