Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.

TitleSetd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
Publication TypeJournal Article
Year of Publication2019
AuthorsMoore SM, Seidman JS, Ellegood J, Gao R, Savchenko A, Troutman TD, Abe Y, Stender J, Lee D, Wang S, Voytek B, Lerch JP, Suh H, Glass CK, Muotri AR
JournalTransl Psychiatry
Date Published2019 01 17
KeywordsAnimals, Autism Spectrum Disorder, Behavior, Animal, Brain, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Magnetic Resonance Imaging, Male, Methyltransferases, Mice, Mice, Knockout, Mutation, Neurons

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5 cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5 cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5 animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5 adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

Alternate JournalTransl Psychiatry
PubMed ID30655503
PubMed Central IDPMC6336863
Grant ListR01 AA022377 / AA / NIAAA NIH HHS / United States
R01 MH108528 / MH / NIMH NIH HHS / United States
R01 MH100175 / MH / NIMH NIH HHS / United States
R01 MH094753 / MH / NIMH NIH HHS / United States
R01 MH109885 / MH / NIMH NIH HHS / United States
U19 MH107367 / MH / NIMH NIH HHS / United States
IRG Funded