Elucidating the role of the autism risk gene Tbr1 in synaptic development in mice

Tbr1, a high-confidence autism spectrum disorder (ASD) risk gene, encodes a T-box transcription factor that plays a central role in the development of early-born cortical excitatory neurons, controlling the identity and connectivity of layer 6 pyramidal neurons. Whether Tbr1 regulates later steps in cortical development is poorly understood.

John Rubenstein’s laboratory recently demonstrated that a reduction in Tbr1 dosage (heterozygous loss of function) disrupts synaptic development of mouse layer 6 neurons and that this synaptic defect can be rescued by increasing WNT signaling¹. As genes regulating synaptic function are also enriched among ASD risk genes, this may be a point of convergence for understanding ASD pathophysiology.

Rubenstein and colleagues propose to elucidate the Tbr1-regulated transcriptional network in deep layers of the developing mouse neocortex, at a stage roughly equivalent to human midfetal development and to analyze synaptic phenotypes in Tbr1 conditional and constitutive mutant mice. In doing so, they expect to provide insights into the biological pathways by which Tbr1 regulates synaptogenesis and synaptic function, improving our understanding of brain development and, potentially, our understanding of the pathophysiology of ASD.

Rubenstein’s team also has preliminary evidence that the synaptic defects in layer 6 of Tbr1 mutant mice can be rescued in vivo by the antipsychotic drug lithium chloride. The team plans to continue to explore the use of this drug along with alternative methods of restoring synaptic structure in Tbr1 mutant mice.

Taken together, the current work promises to provide mechanistic insights into how Tbr1 regulates cortical connectivity and insights into potential therapies for correcting these defects in mice and, potentially, in humans.