Dataset Information

Postnatal immune activation causes social deficits in a mouse model of tuberous sclerosis: Role of microglia and clinical implications.

ABSTRACT: There is growing evidence that prenatal immune activation contributes to neuropsychiatric disorders. Here, we show that early postnatal immune activation resulted in profound impairments in social behavior, including in social memory in adult male mice heterozygous for a gene responsible for tuberous sclerosis complex (Tsc2^+/−), a genetic disorder with high prevalence of autism. Early postnatal immune activation did not affect either wild-type or female Tsc2^+/− mice. We demonstrate that these memory deficits are caused by abnormal mammalian target of rapamycin–dependent interferon signaling and impairments in microglia function. By mining the medical records of more than 3 million children followed from birth, we show that the prevalence of hospitalizations due to infections in males (but not in females) is associated with future development of autism spectrum disorders (ASD). Together, our results suggest the importance of synergistic interactions between strong early postnatal immune activation and mutations associated with ASD.

SUBMITTER: Lopez-Aranda MF

PROVIDER: S-EPMC8448451 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Postnatal immune activation causes social deficits in a mouse model of tuberous sclerosis: Role of microglia and clinical implications.

López-Aranda Manuel F MF Chattopadhyay Ishanu I Boxx Gayle M GM Fraley Elizabeth R ER Silva Tawnie K TK Zhou Miou M Phan Miranda M Herrera Isaiah I Taloma Sunrae S Mandanas Rochelle R Bach Karen K Gandal Michael M Geschwind Daniel H DH Cheng Genhong G Rzhetsky Andrey A White Stephanie A SA Silva Alcino J AJ

Science advances 20210917 38

There is growing evidence that prenatal immune activation contributes to neuropsychiatric disorders. Here, we show that early postnatal immune activation resulted in profound impairments in social behavior, including in social memory in adult male mice heterozygous for a gene responsible for tuberous sclerosis complex (Tsc2+/−), a genetic disorder with high prevalence of autism. Early postnatal immune activation did not affect either wild-type or female Tsc2+/−</i ...[more]

PMID: 34533985

Similar Datasets

Project description:Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant (TscD+/-) mice. TscD+/- mice exhibited impairments in social behaviors, and the severity of impairments was similar to Tsc2+/- mice rather than Tsc1+/- mice. Impairments in social behaviors were rescued by rapamycin treatment in all mutant mice. Gene expression profiles in the brain were greatly altered in TscD+/- mice more than in Tsc1+/- and Tsc2+/- mice. The gene expression changes compared with wild type (WT) mice were similar between TscD+/- and Tsc2+/- mice, and the overlapping genes whose expression was altered in mutant mice compared with WT mice were enriched in the neoplasm- and inflammation-related canonical pathways. The "signal transducer and activator of transcription 3, interferon regulatory factor 1, interferon regulatory factor 4, interleukin-2R α chain, and interferon-γ" signaling pathway, which is initiated from signal transducer and activator of transcription 4 and PDZ and LIM domain protein 2, was associated with impairments in social behaviors in all mutant mice. It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype-phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.

Dataset Information

Postnatal immune activation causes social deficits in a mouse model of tuberous sclerosis: Role of microglia and clinical implications.

Publications

Postnatal immune activation causes social deficits in a mouse model of tuberous sclerosis: Role of microglia and clinical implications.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets