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

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.

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

“…RhoA is one of the proteins that controls neurite outgrowth, and RhoA upregulation was previously implicated in loss of spines and neurite retraction [10,11,14,25,27]. Previously developed genetic autism mouse models (SETD5, UBE3A, SHANK3, Timothy syndrome) also observed reduced neurite outgrowth, sometimes in concert with the reduced synaptic connectivity [27][28][29][30]. The iPSC-derived neurons from Timothy syndrome patients also exhibited dendrite retraction phenotype [27].…”

Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development

“…Newborn mouse primary culture was performed as described elsewhere (Moore et al, 2019). The cells were maintained in Neurobasal medium with GlutaMAX, 1% Gem21 NeuroPlex, 1% NEAA and 1% PS.…”

SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring

“…(legend continued on next page) the transcriptional program necessary for limiting the establishment of synaptic long-term potentiation to physiological levels (Deliu et al, 2018). SETD5 was described as being associated with HDAC3 and with the polymerase-associated factor (PAF) complexes, while its intrinsic enzymatic activity has been neglected so far (Osipovich et al, 2016;Deliu et al, 2018;Moore et al, 2019). Hence, several aspects of SETD5 remain unaddressed, in particular its function in regulating the chromatin state and organization, its importance for RNA transcriptional mechanisms, and the relation between altered gene expression and neuronal deficits.…”