Interneuron Development Is Disrupted in Preterm Brains With Diffuse White Matter Injury: Observations in Mouse and Human

Abstract

Preterm brain injury, occurring in approximately 30% of infants born <32 weeks gestational age, is associated with an increased risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The mechanism of gray matter injury in preterm born children is unclear and likely to be multifactorial; however, inflammation, a high predictor of poor outcome in preterm infants, has been associated with disrupted interneuron maturation in a number of animal models. Interneurons are important for regulating normal brain development, and disruption in interneuron development, and the downstream effects of this, has been implicated in the etiology of neurodevelopmental disorders. Here, we utilize postmortem tissue from human preterm cases with or without diffuse white matter injury (WMI; PMA range: 23 +2 to 28 +1 for non-WMI group, 26 +6 to 30 +0 for WMI group, p = 0.002) and a model of inflammation-induced preterm diffuse white matter injury (i.p. IL-1β, b.d., 10 μg/kg/injection in male CD1 mice from P1–5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed growth of neuronal arbors at this early stage of development. In the mouse, significant reduction in the number of parvalbumin-positive interneurons was observed from postnatal day (P) 10. This decrease in parvalbumin neuron number was largely rectified by P40, though there was a significantly smaller number of parvalbumin positive cells associated with perineuronal nets in the upper cortical layers. Together, these data suggest that inflammation in the preterm brain may be a contributor to injury of specific interneuron in the cortical gray matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants.

Connexin Hemichannel Mimetic Peptide Attenuates Cortical Interneuron Loss and Perineuronal Net Disruption Following Cerebral Ischemia in Near-Term Fetal Sheep

“…There is increasing evidence that injury to cortical interneurons, including loss of PNNs and disruption of inhibitory interneuron circuits, is an important contributor to neurological disability following neonatal brain injury [17,25,26]. The present study demonstrates that blockade of connexin43 hemichannel opening with a mimetic peptide during early recovery from HI in term-equivalent fetal sheep improved survival of cortical GABAergic interneurons and prevented loss of cortical PNNs after 7 days of recovery.…”

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

“…However, it supports in contemporaneous infants the relevance of the WNT pathway using an imaging modality that is currently used to assess injury and predict outcome. Also, we wish to highlight that changes to the grey matter are also evident in preterm born infants, including changes in cortical microstructure (Ball et al, 2013), interneuron distribution (Stolp et al, 2019) and degeneration of axons (Back and Miller, 2014). However, the contribution of axonal injury to diffuse white matter is controversial, although it is evident in necrotic foci that are approximated to occur in only 5% of white matter injury cases (Riddle et al, 2011;Buser et al, 2012).…”

Current Evidence on Cell Death in Preterm Brain Injury in Human and Preclinical Models

“…Recent studies have shown that cortical interneurons development can be disrupted (reduced Abbreviations: 3-MA, 3-methyladenin; ADC, apparent diffusion coefficients; ATG, autophagy-related gene; CASP, caspase; c-CASP, cleaved caspase; cPVL, cystic periventricular leucomalacia; CSF, cerebrospinal fluid; dWMI, diffuse white matter injury; EM, electronic microscopy; EoP, encephalopathy of prematurity; ER, endoplasmic reticulum; FA, fractional anisotropy; GA, gestational age; GM, gray matter reduction; GMH, germinal matrix hemorrhage; HI, hypoxiaischemia; IVH, intraventricular hemorrhage; LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MRI, magnetic resonance imaging; OL, oligodendrocytes; PE, phosphatidylethanolamine; PHH, post-hemorrhagic hydrocephalus; preOL, pre-oligodendrocyte; PVL, periventricular leucomalacia; PWM, periventricular white matter; SCWM, subcortical WM; SVZ, subventricular zone; VPT, very preterm infants; WM, white matter; WMI, white matter injury. number and morphological complexity) in preterm infants with non-cystic WM injury or in inflammatory conditions (Panda et al, 2018;Stolp et al, 2019). Moreover, constant improvement in imaging techniques allows to study and detect microstructural alterations not only in WM but also in GM related to neurodevelopmental disorders (Chau et al, 2013;Nossin-Manor et al, 2013;Kersbergen et al, 2016).…”