Abstract 16609: Characterization of Neurodevelopmental Defects Associated with a Mouse Model of Hypoplastic Left Heart Syndrome

Introduction: Hypoplastic left heart syndrome (HLHS), a congenital heart defect involving left-sided heart structures, is associated with poor neurodevelopmental outcome, with >30% experiencing neurodevelopmental impairment. A mouse model of HLHS showed brain abnormalities, suggesting a shared genetic etiology for brain and cardiac defects in HLHS. Hypothesis: Mutations in Sap130 and Pcdha9 causing HLHS in mice may individually or together cause brain abnormalities and neurobehavioral deficits. Methods and Results: Confocal histopathology and MR imaging was used to analyze the brain in mutant mice that were double Sap130/Pcdha9 homozygous, single Pcdha9 or Sap130 homozygous, or with forebrain targeted Emx1-Cre deletion of a floxed Sap130 allele . Sap130/Pcdha9 and Sap130 mutants exhibited overlapping phenotypes with microcephaly, thin cortex, and defects in the olfactory bulb, cerebellum, corpus callosum, and hippocampus, structures commonly affected in HLHS. RNAseq of Sap130/Pcdha9 mutant brain showed dysregulation of genes mediating learning and memory, long-term potentiation, motor coordination, feeding-processes often affected in HLHS. In the Emx1-Cre forebrain deleted Sap130 mice, forebrain hypoplasia was associated with cortical thinning and hippocampal dysplasia (Fig1 A,B). DTI connectome analysis showed global reduction in neuronal connections. Homozygous Pcdha9 mutant mice, which are adult viable, showed only hippocampal dysplasia, but connectome analysis also showed global reduction in neuronal connections (Fig1 C,D). In line with this, behavioral tests showed deficits in spatial memory acquisition and cued fear conditioning (Fig1 E,F). Conclusions: We showed HLHS associated Pchda9 and Sap130 mutations, individually or together, can cause brain defects with reduced neuronal connections and neurobehavioral deficits. These defects can occur independent of the cardiac lesion, indicating they are not of hemodynamic origin.