TBR1 HAPLOINSUFFICIENCY IMPAIRS DENDRITIC INTEGRATION IN NEOCORTICAL PYRAMIDAL NEURONS VIA REGULATION OF SCN2A

Autism spectrum disorder (ASD) is associated with genetic variation in hundreds of genes. Broadly, these genes encode synaptic proteins or transcriptional regulatory machinery, raising the question of whether and how these disparate gene classes converge to result in common phenotypes within the autism spectrum.
Here, we examine how heterozygous loss of the gene Tbr1—an ASD-associated transcriptional regulator—affects synapse function and dendritic excitability. Tbr1 is among a class of transcriptional regulatory elements that are active in neocortical pyramidal cells. Tbr1 is known to act as a positive regulator of other ASD-associated genes, including those that localize at or near synapses. One major transcriptional target is Scn2a, a high-confidence ASD-associated gene that codes for the sodium channel Na_V1.2. In neocortical pyramidal cells, Na_V1.2 localizes to dendrites, and heterozygous loss of Scn2a impairs dendritic integration and synapse maturation. Thus, we tested whether dendritic integration was similarly impaired in mice heterozygous for Tbr1. In prefrontal cortex layer 5 pyramidal cells, we found that Tbr1 haploinsufficiency impaired dendritic excitability — the ability of dendrites to integrate and transform synaptic input — and that these deficits appear due, in part, to a reduction in Na_V1.2 expression. Interestingly, effects were most overt in the apical tuft dendrite regions most distal to the soma. This suggests that associative inputs impinging on this apical tuft region may be particularly sensitive to Tbr1 expression.
These results highlight emerging evidence suggesting that dysfunction in dendritic excitability may aid in understanding features of neuronal processing affected in ASD.