G. Sanidas, G. Simonti, J. Ghaemmaghami, K. Woyshner, R. Vidva, D. C. Bittel, N. Wolff, M. Triantafyllou, A. Polyviou, C. Byrd, C. Lowe, H. Salisbury, E. Goldstein, A. Sathyanesan, I. Koutroulis, G. O Brien, D. Sidiropoulos, V. Gallo, P. Kratimenos
Preterm survivors often develop motor and socio-cognitive impairments that implicate altered cerebellar development, yet the underlying mechanisms remain poorly understood. A key challenge is that prematurity involves overlapping perinatal insults that converge on the developing brain, making their individual effects difficult to disentangle. Here, we model two major prematurity-associated insults, maternal immune activation (MIA) and neonatal hypoxia (Hx), in mice. By controlling timing and sequence, we define how these insults shape cerebellar assembly during rapid maturation. Comparative analysis with human tissue confirmed that these insults recapitulate key features of the human preterm cerebellum, establishing the translational validity of this model for dissecting insult-specific outcomes. Behavioral and kinematic profiling revealed divergent motor and social phenotypes, which we traced to insult-specific cerebellar remodelling. Hypoxia compromised both granule cell maturation in the internal granule layer and the principal excitatory afferents to Purkinje cells, a circuit state that manifested as impaired motor execution and stereotyped, sensory-disengaged social investigation. Maternal immune activation, by contrast, expanded the granule cell progenitor layer and reduced Purkinje cell dendritic complexity, a phenotype that preserved social preference but reorganized the kinematic structure of social investigation. When hypoxia followed maternal immune activation, it acted on this primed substrate to produce a distinct state in which the features established by prior inflammation were compounded by granule cell proliferative arrest, progressive mitochondrial dysfunction, and aberrant, hyper-interactive social investigation. Together, these findings reframe prematurity-associated insults as cerebellar reprogramming events shaped by both the identity and sequence of insults, linking distinct mechanistic substrates to divergent neurodevelopmental outcomes.