Abstract T P241: Glial Responses in a Pediatric Model of Ischemic Stroke

Abstract

Pediatric arterial ischemic stroke affects hundreds of children in the United States each year, with a majority of surviving children suffering long-term neurologic deficit. Initial studies suggest that recovery from stroke is greater among juveniles compared to neonates or adults. We have developed a middle cerebral artery occlusion (MCAO) mouse model of pediatric stroke in order to understand the cellular responses unique to the juvenile developmental time period. One strikingly understudied aspect of stroke, especially in juvenile subjects, is its impact on glia, in particular myelinating glia. Therefore, the glial responses following experimentally-induced stroke in juvenile mice were investigated. Methods: P20-25 mice were subjected to 45 min MCAO with an intraluminal filament. Animals were analyzed at 24 hr, 3, 7 and 30 days of recovery. Results: Due to the high metabolic activity of myelinating oligodendrocytes during pediatric development, we hypothesized that oligodendrocytes would be particularly sensitive to ischemia. Surprisingly, mature oligodendrocytes and gross myelin production were unaffected during the acute (24 hr and 3 d post MCAO) and subacute (7 d) recovery phases. However, during the chronic (30 d) phase, some myelin debris and signs of mild axon pathology were detected in the lateral striatum, where gliosis was most severe. GFAP immunoreactivity steadily increased in the lesioned striatum from 24 hr to 30 d following MCAO. Similarly, Iba1-positive microglia and NG2-positive cells proliferated in the lesioned area 24 hr after stroke, and remained increased after 30 d. Adult mice subject to identical ischemic insult resulted in decreased numbers of oligodendrocytes, severe axon pathology, and significantly greater tissue loss. Conclusions: Together, these results suggest that myelinating oligodendrocytes in the pediatric brain are resistant to the initial ischemic insult. Furthermore, retaining healthy oligodendrocytes after stroke could serve an important role in maintaining axon integrity and limiting long-term tissue loss after stroke. Understanding the unique cellular responses in the juvenile brain could yield valuable insight into enhancing cellular resistance and promoting recovery after ischemia.