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A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy
Published on: November 3, 2016
Neonatal subarachnoid hemorrhage disrupts multiple aspects of cerebellar development
David F Butler1, Jonathan Skibo2, Christopher M Traudt3
1Division of Pediatric Critical Care, Seattle Children's Hospital, University of Washington, Seattle, WA, United States.
Insights
Cerebellar hemorrhagic injury in extremely low gestational age neonates (ELGANs) impairs brain development. Early intervention with Ketoprofen did not protect against neurodevelopmental deficits in a neonatal mouse model.
Area of Science:
- Neonatal neurology
- Cerebellar development
- Neuroprotection strategies
Background:
- Survival rates for extremely low gestational age neonates (ELGANs) have improved, but neurodevelopmental dysfunction remains a significant concern.
- Cerebellar hemorrhagic injury (CHI) is increasingly recognized in ELGANs and linked to neurological deficits, yet its mechanisms are poorly understood.
Purpose of the Study:
- To investigate the acute and long-term effects of early isolated posterior fossa subarachnoid hemorrhage (SAH) in a neonatal mouse model.
- To explore the potential neuroprotective effects of Ketoprofen in mitigating CHI-induced cerebellar damage.
Main Methods:
- Developed a novel mouse model of early isolated posterior fossa subarachnoid hemorrhage (SAH) on postnatal day 6.
- Assessed cerebellar structural changes (EGL proliferation, PC density, BG fiber crossings) at P8 and P42.
- Evaluated motor function and learning using Rotarod and inverted screen assays at P35-38.
- Administered Ketoprofen to assess its impact on neuroprotection post-CHI.
Main Results:
- SAH led to decreased external granular layer (EGL) proliferation and thinning, reduced Purkinje cell (PC) density, and increased Bergmann glial (BG) fiber crossings at P8.
- Long-term effects at P42 included decreased PC density, reduced molecular layer interneuron (MLI) density, and increased BG fiber crossings.
- No significant motor or learning deficits were observed in the Rotarod or inverted screen assays.
- Ketoprofen treatment did not significantly alter the observed outcomes after CHI.
Conclusions:
- Early isolated SAH causes significant structural damage to the developing cerebellum in neonatal mice.
- Neuroinflammation, targeted by Ketoprofen, may not be the primary mechanism driving CHI-induced neurodevelopmental deficits.
- Further research is needed to understand CHI's disruption of cerebellar development and identify 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.
