Cerebral ischemia can occur at any stage in life, but clinical consequences greatly differ depending on the developmental stage of the affected brain structures. Timing of the lesion occurrence seems to be critical, as it strongly interferes with neuronal circuit development and determines the way spontaneous plasticity takes place. Translational stroke research requires the use of animal models as they represent a reliable tool to understand the pathogenic mechanisms underlying the generation, progression, and pathological consequences of a stroke. Moreover, in vivo experiments are instrumental to investigate new therapeutic strategies and the best temporal window of intervention. Differently from adults, very few models of the human developmental stroke have been characterized, and most of them have been established in rodents. The models currently used provide a better understanding of the molecular factors involved in the effects of ischemia; however, they still hold many limitations due to matching developmental stages across different species and the complexity of the human disorder that hardly can be described by segregated variables. In this review, we summarize the key factors contributing to neonatal brain vulnerability to ischemic strokes and we provide an overview of the advantages and limitations of the currently available models to recapitulate different aspects of the human developmental stroke.

Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a “maladaptive” strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke.

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