Prematurity Reprograms Cerebellar Development and Long-Term Behavior

Premature survivors are at risk for motor and socio-cognitive impairments, implicating cerebellar dysfunction. However, underlying mechanisms remain unclear due to the heterogeneity of preterm insults, the most prominent being prenatal maternal immune activation (MIA) and neonatal hypoxia (Hx). To examine how individual or sequential insults affect cerebellar function, we utilized a double-hit (DH) mouse model that integrates both exposures. Comparative analysis showed that this model recapitulates key features of the human preterm cerebellum, allowing systematic evaluation of insult-specific outcomes. Isolated Hx triggered S-phase arrest in mature granule cells, disrupted Purkinje cell synaptic integration, and led to both motor and social deficits. In contrast, when Hx followed MIA (DH), it delayed granule cell maturation with G2-phase retention and triggered progressive mitochondrial dysfunction. While DH mice developed motor-cognitive impairments, sociability was preserved. These findings underscore the multiplicity of neurodevelopmental outcomes in prematurity, shaped by timing and interaction of early-life insults.