Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism.

Abstract

Gene and protein expression of BTBR T+ Itpr3tf /J (BTBR) mice with autistic-like behaviours were compared with the C57BL/6J strain, which is considered to have normal immunity and behaviour. Notch signalling pathway was constitutively activated in the immune system and liver of BTBR T+ Itpr3tf /J (BTBR) mice. Notch ligand 4 (Dll4), Notch receptors (Notch1 Notch2 and Notch3) and recombination signal binding protein for immunoglobulin κ j region (RBPJ) were increased both at gene and protein levels in BTBR spleens and thymi. Notch downstream transcriptional factors, Tbx21, Gata3, Rorc and FoxP3 were increased in BTBR spleens, Gata3 and FoxP3 were increased in BTBR thymi and BTBR mice have a high blood CD4/CD8 T cell ratio. Reduced nucleotide excision repair ability in BTBR spleens was associated with increased 8-oxoguanine, Ogg1 inhibition, an enhanced level of apoptotic thymocytes and higher expression of GATA-3. Ogg1 inhibition and enhanced GATA-3 expression also were detected in BTBR brain. Notch signal promoted mitochondrial dynamics switching to enhanced fission with an increased number and mass of mitochondria in immune cells of BTBR mice, but not in livers and brains. Constitutive influences on mitochondria exist in this mouse model of autism spectrum disorder; similar outcomes from environmental exposures might occur perinatally in susceptible individuals to affect the development of autism.