Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth

Shaw, Julia C.; Palliser, Hannah K.; Dyson, Rebecca M.; Berry, Mary J.; Hirst, Jonathan J.

doi:10.1016/j.ijdevneu.2017.10.002

Cited by 20 publications

(32 citation statements)

References 75 publications

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“…6 In our clinically relevant guinea pig model, 13 we have shown premature loss of allopregnanolone significantly decreases myelination in the hippocampus, subcortical white matter and cerebellum, key areas involved in memory and learning, and that these deficits are maintained until juvenility. 6,[14][15][16][17] Interestingly, the deficits observed are associated with disturbances in behaviour, supporting a role for reduced allopregnanolone in the behavioural changes seen in this model. 16,17 Neurosteroids have been shown to exert neuroprotective effects following damage to neurons and glia by preventing apoptosis and inflammation, and increasing re-myelination and regenerative mechanisms.…”

Section: Introductionsupporting

confidence: 53%

Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs

et al. 2018

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Section: Introductionsupporting

confidence: 53%

Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs

et al. 2018

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“…; Shaw et al . , , ) opens a critical area of developmental research in which the consequence of curtailed progesterone exposure and differences in substrate availability in preterm‐delivered offspring compared to fetuses at the same postconceptional age can be explored.…”

Section: Introductionmentioning

confidence: 99%

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Morrison

Botting

Darby

et al. 2018

The Journal of Physiology

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Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.

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“…It is now suggested that disruptions to cerebellar development, which can occur as a result of late gestation compromises such as preterm birth, can have a major impact on the region of the brain to which it projects . In our studies in guinea pig neonates that were born preterm, the Purkinje cells were smaller and, in later life, the expression of the GABA‐synthesising enzyme GAD67 was reduced in cerebellar lobules IX and X, indicating that there may be long‐lasting reduced levels of GABA and increased levels of glutamate. The results also suggested that excitatory input onto Purkinje cells was reduced following preterm delivery because the relative width of the internal granule cell layer was reduced in both sexes .…”

Section: Evidence For Imbalance Following Perinatal Compromisementioning

confidence: 55%

“…In our studies in guinea pig neonates that were born preterm, the Purkinje cells were smaller and, in later life, the expression of the GABA‐synthesising enzyme GAD67 was reduced in cerebellar lobules IX and X, indicating that there may be long‐lasting reduced levels of GABA and increased levels of glutamate. The results also suggested that excitatory input onto Purkinje cells was reduced following preterm delivery because the relative width of the internal granule cell layer was reduced in both sexes . The internal granule cell layer comprises the glutamatergic neurones of the cerebellum for which the primary role is excitation of Purkinje cells.…”

Section: Evidence For Imbalance Following Perinatal Compromisementioning

confidence: 56%

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Shaw

Crombie

Zakár

et al. 2019

J Neuroendocrinology

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Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.

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Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth

Cited by 20 publications

References 75 publications

Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs

Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

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