Prematurity Reprograms Cerebellar Development and Long-Term Behavior
Premature survivors face increased risk of motor and socio-cognitive impairments, implicating cerebellar dysfunction, though the underlying mechanisms remain unclear. The cerebellums rapid development in late gestation makes it especially vulnerable to preterm birth. This study uses a double-hit (DH) mouse model combining maternal immune activation (MIA) and neonatal hypoxia (Hx), to mimic the sequential insults associated with prematurity. Validation with human postnatal cerebellar tissue demonstrated that the DH model recapitulates key structural and molecular features of early-life cerebellar injury. We characterized the cerebellar response to Hx, identifying motor and social deficits associated with S-phase arrest of mature granule cells and impaired synaptic integration by Purkinje cells. Conversely, DH mice exhibited delayed granule cell progenitor maturation, G2-phase retention, and progressive neuronal mitochondrial dysfunction, leading to motor-cognitive impairments while preserving sociability through distinctive and adaptive social interaction kinematics. These findings reveal insult-specific mechanisms of cerebellar developmental disruption and guide potential neuroprotective strategies.