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.
Highlights
While preterm birth has a multifactorial etiology, it is widely recognized as being precipitated by pro-inflammatory events, and these vulnerable infants are at risk of further exposure to inflammation and infection
Stereological assessment of cell number in the frontal cortex of the developing human brain showed no change in the total number of neurons, identified by HuC/HuD immunoreactivity, with 53,104 ± 11,009 immunopositive cells/mm2 found in the control brains (n = 5), and 52,120 ± 6,327 cells/mm2 in the cortex of the white matter injury cases (n = 4)
There were no statistical differences in the number of cells in either interneuron (SST or neuropeptide Y (NPY)) subpopulation between preterm infants with or without white matter injury (n = 5 for both)
Summary
While preterm birth has a multifactorial etiology, it is widely recognized as being precipitated by pro-inflammatory events (reviewed by Hagberg et al, 2015), and these vulnerable infants are at risk of further exposure to inflammation and infection. Inflammation is a risk factor in the development of neurodevelopmental disorders (Hagberg et al, 2012; Jiang et al, 2018), such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), childhood epilepsy and disorders of learning, and cognition and emotional development. It is possibly unsurprising that up to 30% of preterm born infants are diagnosed with a neurodevelopmental disorders in childhood (Marlow et al, 2005; Wood et al, 2005; Johnson et al, 2010; Franz et al, 2018). The development of therapies is hampered by the fact that the neuropathology of developmental disorders is as mixed as the diagnosis, varying both between and within specific clusters of disorders
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