Neurotoxic Reactive Astrocytes Drive Defective Myelination in Acute Perinatal White Matter Injury.

Introduction: Acute perinatal white matter injury (apWMI) is the most common form of brain injury in preterm infants, yet the mechanisms underlying neurologic dysmaturation in this disease are far from understood. Reactive astrocytes are a hallmark of apWMI, but the roles that astrocytes play in disease pathogenesis remain unclear. Studies in the mature brain highlight the formation of molecularly distinct reactive astrocyte subtypes in response to brain injury, some that are strongly neurotoxic and others that mediate brain repair. The current research project tests the hypothesis that neurotoxic reactive astrocytes (nrAs) form in apWMI and are drivers of disease outcomes.
Methods: We tested the formation of neurotoxic reactive astrocytes across multiple rodent apWMI models. apWMI was confi rmed using immunohistochemistry for myelin basic protein at postnatal day 11. nrAs were identifi ed using in situ Hybridization (ISH) for nrA marker C3. Microfl uidic qRT-PCR of mRNA isolated from immunopanned and FACS purifi ed primary rodent astrocytes evaluated the expression of a panel of established reactive astrocyte subtype-specifi c genes. C1q-/-, Il1-a-/-, TNF-/- mutant mice were used to investigate the necessity of nrAs for myelination defects.
Results: We demonstrate the formation of neurotoxic reactive astrocytes following acute perinatal brain insult in rodent apWMI disease models. These cells form within the fi rst 24 hours of brain injury. C1q-/-, Il1-a-/-, TNF-/- transgenic mice unable to form nrAs display a signifi cant reduction in myelination defects in periventricular white matter after injury
compared with wildtype controls.
Conclusion: Our experiments provide evidence that neurotoxic reactive astrocytes not only form following acute infl ammatory/hypoxic perinatal brain injury but also appear to play a causal role in the production of myelination defects associated with this disease. This fi nding opens the door to investigating nrAs as therapeutic targets in apWMI. Ongoing experiments aim to defi ne a therapeutic window for rescuing myelination through the modulation of nrAs and to confi rm formation of nrAs in human postmortem perinatal brain specimens aff ected by apWMI.