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Neonatal Subarachnoid Hemorrhage Disrupts Multiple Aspects of Cerebellar Development
Insights
Cerebellar hemorrhagic injury in extremely low gestational age neonates (ELGANs) impairs brain development, leading to reduced neuron density. Anti-inflammatory treatment did not improve outcomes in this novel mouse model.
Area of Science:
- Neuroscience
- Neonatal Research
- Developmental Biology
Background:
- Survival rates for extremely low gestational age neonates (ELGANs) have improved, but neurodevelopmental dysfunction remains a concern.
- Cerebellar hemorrhagic injury (CHI) is increasingly recognized in ELGANs and linked to neurological deficits, yet underlying mechanisms are unclear.
Approach:
- Developed a novel mouse model of early isolated posterior fossa subarachnoid hemorrhage (SAH) in neonatal mice.
- Investigated acute (P8) and long-term (P42) effects of CHI on cerebellar development and cellular structure.
- Assessed motor function and learning using Rotarod and inverted screen assays, and evaluated the efficacy of Ketoprofen treatment.
Key Points:
- SAH induced decreased external granular layer proliferation, thinning, reduced Purkinje cell density, and increased Bergmann glial fiber crossings acutely.
- Long-term CHI effects included decreased Purkinje cell and molecular layer interneuron density, and increased Bergmann glial fiber crossings.
- Motor and learning assays showed no significant deficits, and Ketoprofen treatment did not provide neuroprotection.
Conclusions:
- CHI significantly disrupts cerebellar developmental programming in neonatal mice.
- Neuroinflammation may not be the primary target for neuroprotection against CHI in this model.
- Further research is needed to understand CHI mechanisms and develop effective therapeutic strategies for ELGANs.
Abstract:
Over the past decade, survival rates for extremely low gestational age neonates (ELGANs; <28 weeks gestation) has markedly improved. Unfortunately, a significant proportion of ELGANs will suffer from neurodevelopmental dysfunction. Cerebellar hemorrhagic injury (CHI) has been increasingly recognized in the ELGANs population and may contribute to neurologic dysfunction; however, the underlying mechanisms are poorly understood. To address this gap in knowledge, we developed a novel model of early isolated posterior fossa subarachnoid hemorrhage (SAH) in neonatal mice and investigated both acute and long-term effects. Following SAH on postnatal day 6 (P6), we found significant decreased levels of proliferation with the external granular layer (EGL), thinning of the EGL, decreased Purkinje cell (PC) density, and increased Bergmann glial (BG) fiber crossings at P8. At P42, CHI resulted in decreased PC density, decreased molecular layer interneuron (MLI) density, and increased BG fiber crossings. Results from both Rotarod and inverted screen assays did not demonstrate significant effects on motor strength or learning at P35-38. Treatment with the anti-inflammatory drug Ketoprofen did not significantly alter our findings after CHI, suggesting that treatment of neuro-inflammation does not provide significant neuroprotection post CHI. Further studies are required to fully elucidate the mechanisms through which CHI disrupts cerebellar developmental programming in order to develop therapeutic strategies for neuroprotection in ELGANs.
