Can Neonatal Systemic Inflammation and Hypoxia Yield a Cerebral Palsy-Like Phenotype in Periadolescent Mice?

Cerebral palsy (CP) is one of the most common childhood-onset motor disabilities, attributed to injuries of the immature brain in the foetal or early postnatal period. The underlying mechanisms are poorly understood, rendering prevention and treatment strategies challenging. The aim of the present study was to establish a mouse model of CP for preclinical assessment of new interventions. For this purpose, we explored the impact of a double neonatal insult (i.e. systemic inflammation combined with hypoxia) on behavioural and cellular outcomes relevant to CP during the prepubertal to adolescent period of mice. Pups were subjected to intraperitoneal lipopolysaccharide (LPS) injections from postnatal day (P) 3 to P6 followed by hypoxia at P7. Gene expression analysis at P6 revealed a strong inflammatory response in a brain region-dependent manner. A comprehensive battery of behavioural assessments performed between P24 and P47 showed impaired limb placement and coordination when walking on a horizontal ladder in both males and females. Exposed males also displayed impaired performance on a forelimb skilled reaching task, altered gait pattern and increased exploratory activity. Exposed females showed a reduction in grip strength and traits of anxiety-like behaviour. These behavioural alterations were not associated with gross morphological changes, white matter lesions or chronic inflammation in the brain. Our results indicate that the neonatal double-hit with LPS and hypoxia can induce subtle long-lasting deficits in motor learning and fine motor skills, which partly reflect the symptoms of children with CP who have mild gross and fine motor impairments.