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Transl Psychiatry. 2019 Jan 17;9(1):24. doi: 10.1038/s41398-018-0344-y.

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

Author information

1
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
2
Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
3
Department of Cellular and Molecular Medicine, School of Medicine, Universityof California, San Diego, La Jolla, CA, USA.
4
Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
5
Neurosciences and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada.
6
Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
7
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
8
Neurosciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
9
5Halıcıoğlu Data Science Institute, University of California, San Diego, La Jolla, CA, USA.
10
Kavli Institute for Brain and Mind, La Jolla, CA, USA.
11
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
12
Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA. muotri@ucsd.edu.
13
Department of Cellular and Molecular Medicine, School of Medicine, Universityof California, San Diego, La Jolla, CA, USA. muotri@ucsd.edu.
14
Kavli Institute for Brain and Mind, La Jolla, CA, USA. muotri@ucsd.edu.
15
Rady Children's Hospital San Diego, San Diego, CA, USA. muotri@ucsd.edu.
16
Stem Cell Program, University of California, San Diego, La Jolla, CA, USA. muotri@ucsd.edu.
17
Center for Academic Research and Training in Anthropogeny (CARTA), University of California, San Diego, La Jolla, CA, USA. muotri@ucsd.edu.

Abstract

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.

PMID:
30655503
PMCID:
PMC6336863
DOI:
10.1038/s41398-018-0344-y
[Indexed for MEDLINE]
Free PMC Article

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