[P2.04]: Autism‐like behaviors in BTBR T+tf/J mice are not attributable to early maternal environment or corpus callosum absence

Abstract

Using a P7 rat model of hypoxic-ischemic (HI) brain injury we have shown that exposure to hypoxia and hyperoxia (HHI) results in generation of reactive oxygen species, inflammation and cell death-all risk factors for subsequent deficits in neuronal development and function. Hyperoxia increases oxidative stress that can trigger inflammatory cascades, neutrophil activation, and brain microvascular injury. Our experiments utilize a modified version of the Rice-Vanucci model of perinatal hypoxia-ischemia in Wistar rat pups that undergo exposure to 100% oxygen. By using T2weighted magnetic resonance imaging we documented enhanced cortical lesions in HHI animals. Electrochemical monitoring showed bursts of superoxide during 100% oxygen resuscitation. Western blot analyses showed increased cell death measured by cleaved caspase 3 and cytosolic oligonucleosomes, and augmented IL-1 signalling above and beyond levels reported for HI alone. Multiplex antibody cytokine assay demonstrates a spectrum of pro-inflammatory cytokines elevated at 24 h post injury. Consistent with the observed increases in oxidative stress components in the HI rat pups resuscitated with 100% oxygen, there was an increase in COX-2 levels likely to account in part for the increase in oxidative stress. In 80% of preterm infants, the common view is that the benefits of oxygen therapy outweigh the risks. We have shown deficits in attention, motor, visual-motor, and executive processing skills in preterm infants otherwise considered ''healthy,'' but these are not apparent before entry into formal learning settings [Smith et al., 2008. Int. J. Dev. Neurosci. 26 (1): 125-131]. Few clinical studies have attempted to target improving outcomes in this large preterm population. These deficits may be accounted for by inflammation caused by the use of 100% oxygen resuscitation. Our long-term goal is to guide clinical trials of oxygen resuscitation by exploring its consequences in the P7 rat model of HI and developing novel interventions that will enhance benefits while decreasing inflammatory consequences.Autism is a neurodevelopmental disorder of complex etiology. Both genetic and environmental factors have been implicated. BTBR T+tf/J (BTBR) is an inbred strain of mice that displays social deficits and repetitive behaviors analogous to the first and third defining symptoms of autism, representing a promising mouse model for autism. In searching for the causes of the autism-like phenotypes in BTBR, we tested possible hypotheses: (1) early postnatal maternal environment, and (2) the complete absence of a corpus callosum (CC), in the BTBR brain.To test the maternal hypothesis, entire litters of pups were cross-fostered to either a dam of the same strain or one of the opposite strain, within 24 h after birth. Offspring were tested for juvenile play at postnatal day 21 (PND21), for sociability and selfgrooming between 8 and 11 weeks. Results indicate that crossfostering had no effect on play behaviors in juveniles of, and did not affect sociability and self-groomin...