Interneuron development is disrupted in preterm brains with diffuse white matter injury: observations in mouse and human

Helen B. Stolp; Bobbi Fleiss; Yoko Arai; Veena Supramaniam; Regina Theresa Vontell; Sebastian Britles; Abi Yates; Aradhna Baburamani; Claire Thornton; Mary Rutherford; A. David Edwards; Pierre Gressens

doi:10.3389/fphys.2019.00955

Interneuron development is disrupted in preterm brains with diffuse white matter injury: observations in mouse and human

Helen B. Stolp, Bobbi Fleiss, Yoko Arai, Veena Supramaniam, Regina Theresa Vontell, Sebastian Britles, Abi Yates, Aradhna Baburamani, Claire Thornton, Mary Rutherford, A. David Edwards, Pierre Gressens

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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 grey 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 aetiology of neurodevelopmental disorders. Here we utilise post-mortem 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., 10µg/kg/injection in male CD1 mice from P1-5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed development of neuronal arbours 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 grey matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants.

Original language	English
Article number	955
Journal	Frontiers in Physiology
Volume	10
Issue number	JUL
Early online date	30 Jul 2019
DOIs	https://doi.org/10.3389/fphys.2019.00955
Publication status	E-pub ahead of print - 30 Jul 2019

Keywords

Human
Mouse
Neuroinflammation
Parvalbumin
Perineuronal nets

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Interneuron development is disrupted_STOLP_Accepted9July2019_GOLD AAMAccepted author manuscript, 2.14 MBLicence: CC BY
Interneuron development is disrupted_STOLP_Accepted9July2019_GOLD VoR (CC BY)Final published version, 2.57 MBLicence: CC BY

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Stolp, H. B., Fleiss, B., Arai, Y., Supramaniam, V., Vontell, R. T., Britles, S., Yates, A., Baburamani, A., Thornton, C., Rutherford, M., Edwards, A. D., & Gressens, P. (2019). Interneuron development is disrupted in preterm brains with diffuse white matter injury: observations in mouse and human. Frontiers in Physiology, 10(JUL), Article 955. Advance online publication. https://doi.org/10.3389/fphys.2019.00955

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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 grey 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 aetiology of neurodevelopmental disorders. Here we utilise post-mortem 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., 10µg/kg/injection in male CD1 mice from P1-5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed development of neuronal arbours 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 grey matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants. ",

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AU - Britles, Sebastian

AU - Yates, Abi

AU - Baburamani, Aradhna

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AU - Rutherford, Mary

AU - Edwards, A. David

AU - Gressens, Pierre

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AB - 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 grey 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 aetiology of neurodevelopmental disorders. Here we utilise post-mortem 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., 10µg/kg/injection in male CD1 mice from P1-5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed development of neuronal arbours 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 grey matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants.

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Interneuron development is disrupted in preterm brains with diffuse white matter injury: observations in mouse and human

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