A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice

Abstract

Mutations in Tbr1, a high-confidence ASD (autism spectrum disorder)-risk gene encoding the transcriptional regulator TBR1, have been shown to induce diverse ASD-related molecular, synaptic, neuronal, and behavioral dysfunctions in mice. However, whether Tbr1 mutations derived from autistic individuals cause similar dysfunctions in mice remains unclear. Here we generated and characterized mice carrying the TBR1-K228E de novo mutation identified in human ASD and identified various ASD-related phenotypes. In heterozygous mice carrying this mutation (Tbr1+/K228E mice), levels of the TBR1-K228E protein, which is unable to bind target DNA, were strongly increased. RNA-Seq analysis of the Tbr1+/K228E embryonic brain indicated significant changes in the expression of genes associated with neurons, astrocytes, ribosomes, neuronal synapses, and ASD risk. The Tbr1+/K228E neocortex also displayed an abnormal distribution of parvalbumin-positive interneurons, with a lower density in superficial layers but a higher density in deep layers. These changes were associated with an increase in inhibitory synaptic transmission in layer 6 pyramidal neurons that was resistant to compensation by network activity. Behaviorally, Tbr1+/K228E mice showed decreased social interaction, increased self-grooming, and modestly increased anxiety-like behaviors. These results suggest that the human heterozygous TBR1-K228E mutation induces ASD-related transcriptomic, protein, neuronal, synaptic, and behavioral dysfunctions in mice.

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

“…However, the preference (Fig. 3b), as previously described [25,32]. Note that the decrease was found to be statistically significant, either with or without an outlier (see Table S1 for details).…”

“…The apparatus consists of two separate chambers (light, 21 × 29 × 20 cm, a white acryl box with no lid on top for video recording; dark, 21 × 13 × 20 cm, a black acryl box with a lid on top) as previously described [23,25]. The light chamber was illuminated at 180 lx.…”

“…A gray Plexiglas box (30 × 30 × 30 cm) was used to measure social interaction between mouse pairs, as previously described [24,25]. Light intensity in the testing chamber was 40 lx.…”

Linking Autism Risk Genes to Disruption of Cortical Development

“…Further, observations in human stem cell-derived models (e.g., organoids) will be key to identify species-specific alterations that define the unique features of social behavior in humans. CHD2 proliferation KO mice [189] PTEN survival KO mice [193] TBR1 lamination KO mice [70,77] Author…”

Anterior Commissure Regulates Neuronal Activity of Amygdalae and Influences Locomotor Activity, Social Interaction and Fear Memory in Mice

“…TBR1 regulates the expression of a set of genes controlling cell adhesion-including Cntn2, Ntng1, and Cdh8-in the basolateral amygdalae (BLA), thereby mediating axonal projection of BLA neurons to the contralateral side via the AC (Huang et al, 2014;Chuang et al, 2015). Importantly, haploinsufficiency or ASD-linked mutation of Tbr1 also results in autism-like behaviors in mice, including reduced social interaction, impaired amygdala-dependent associative memory and disrupted olfactory discrimination (Huang et al, 2014(Huang et al, , 2019aYook et al, 2019), highlighting the relevance of TBR1 deficiency in ASD and reinforcing the potential role of the AC in neuropsychiatric disorders.…”