Long-term neurodevelopmental disorders in mice with apneas during prematurity

Abstract

Epidemological evidence points towards a link between the severity of apneas of prematurity and developmental disorders. However, the causality in this relation has not yet been established. In this study, we made use of a genetic mouse model (Phox2b) that is characterized by an increased apnea time (approximately 6-fold at age P5 compared to wildtype littermates) during normoxia. These breathing problems are, however, confined to 2 to 5 days of postnatal age (≈ severe to moderate prematurity in humans) and mice survive normally without ventilatory support. Furthermore, Phox2b is not expressed in higher brain areas, thus excluding direct effects of the mutation on cognitive development. The described phenotype is particularly useful in light of our interest in the consequences of apneas of prematurity on cognitive functioning. To address this issue, we conducted a behavioural test battery in Phox2b adult mice. We conducted a behavioural study in a genotype (Phox2b heterozygote (HZ) vs wildtype (WT))- and gender-mixed group of adult mice ( N =37). Neuromotor performance (rotarod, grip strength) and cage activity were tested, as well as anxiety and exploration (open field, social exploration and elevated plus maze), and learning and memory (passive avoidance learning and Morris water maze). Phox2b HZ mice showed no differences in weight, nor alterations in neuromotor performance or activity level compared to controls. During the open field and social exploration tests Phox2b HZ exhibited significantly less exploratory behaviour than WT. This behavioural observation was also confirmed in the elevated plus maze. Passive avoidance learning was abolished in a subgroup of Phox2b heterozygotes. Moreover, we found that Phox2b HZ mice were slower to acquire learning in the Morris water maze and displayed small but significant memory deficits in both Morris water maze protocols we applied. In this study, we investigated the long term effects of postnatal apneas by conducting a behavioural study on adult Phox2b mice. We found important deficits in exploratory behaviour, and learning and memory functioning in Phox2b HZ. Since Phox2b is not expressed in higher brain regions which are involved in behavioural tests, these differences are likely to arise from neonatal apneas.