Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity

Published in Neuron, 2018

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[General Summary]

In mice, if you reduce the amount of a particular gene, Tbr1, at a specific time the brain does not form layers as expected and some neurons look and act differently (when compared to mice with normal levels of this gene). However, if you increase the amount of another associated gene, Wnt7b, some of these problems are less severe. This is particularly interesting because in people with autism spectrum disorder (ASD), Tbr1 is commonly a gene that is mutated and doesn’t work properly. Although many hurdles remain before therapies for ASD patients exist, this study is an import first step.


This study explores a how conditional deletion of mouse Tbr1 in cortical layer 6, at a developmental interval roughly equivalent to human mid-fetal stages, alters neuronal identity and function in homozygous and heterozygous mutants. Tbr1, a transcription factor, is a high-confidence autism spectrum disorder (ASD) risk gene that affects the expression of several other ASD-associated genes. Therefore, it is an intriguing target for exploring changes in gene expression, synaptic activity and morphology, and behavior upon mutation. Although previous work has investigated changes with homozygous mutations or deletions, there is less known about the effects of a heterozygous deletion late in gestation.

Results indicate that Tbr1 heterozygous mutant neurons take on a hybrid layer 5 and layer 6 identity based on their gene expression profile, dendritic pattern, and physiology. Gene expression data (RNA-seq and ISH) denomstrates Tbr1 promotes expression of layer 6 markers and represses expression of layer 5 identity regulators. Apical dendrites in wild-type controls extend to layer 4 by P3; however, in Tbr1 homozygotes extension occurs to layer 1 by P3 and Tbr1 heterozygotes show extensions to both layer 1 and layer 2/3 by P3. Neurons from both the Tbr1 heterozygous and homozygous mice have reduced excitatory and inhibitory synaptic density as well as spontaneous excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs). Restoring expression of Wnt7b (a direct Tbr1 target) largely rescues the reduction in both excitatory and inhibitory synapse numbers in vitro and in vivo.

Currently, there are no effective somatic treatments for most core deficits of ASD. More broadly, there are no current treatments for neuropsychiatric illness in humans that restore normal biology. The ability to successfully restore synapse numbers by expressing Wnt7b may provide a possible avenue to restoring synapse numbers in humans with Tbr1 mutations using small-molecule WNT7B agonists. In short, these observations provide an important initial step in conceptualizing rational therapies for ASD patients, although critically important hurdles remain.