Hypoxia-Ischemia During a Neonatal Sensitive Period Alters Purkinje Neuron Dendritic Complexity Differently in Male and Female Rats

Abstract Perinatal hypoxia-ischemia (HI) is a major health issue with no effective therapies beyond head cooling. Notably, male infants are at a greater risk for HI and exhibit more extreme deficits than females. Extensive clinical evidence indicates that perinatal HI impacts the developing cerebellum, yet this region has been largely ignored in preclinical models. Using a modified version of the Rice-Vannucci rat model for HI injury at postnatal day 10, we find reductions in dendritic complexity of Purkinje neurons in males one week later. Females exhibited modest but opposite effects, with slight increases in dendritic complexity, based on Sholl analysis. A custom-made NanoString panel for quantifying mRNAs associated with development, inflammation, and sex differences found almost no commonality in the response to HI in males versus females, with males up-regulating genes associated with microglia activity whereas females increased expression of a protective complement protein, but also of enzymes associated with endocannabinoids and prostaglandins. Both sexes exhibited a reduction in the GABA-synthetic enzymes, GAD-65 and GAD-67, after HI, suggesting increased excitotoxicity, but why males suffered more damage to the Purkinje neurons is unknown.