The transcription factor Tbr1 has been convincingly identified as an autism risk factor, and researchers have previously shown that its function is critical for the typical development of deep-layer cortical neurons. A new study in mice sheds further light on its role in synapse and dendrite development and identifies a number of downstream targets and possible avenues for therapy.

Supported in part by a Research Award to SFARI Investigator John Rubenstein, the work used mouse lines that are constitutively heterozygous for Tbr1, or lack one copy of the gene only in layer 5 or layer 6 neurons of the cortex. Single-cell RNA sequencing of layer 5 Tbr1-deficient neurons identified a number of transcripts whose expression was significantly altered, including Kif1a, Gsk3b, Wnt7b, Ctnnb1, Ank2 and Smarcc2. Additional analyses showed a reduced number of excitatory and inhibitory synapses in deep-layer neurons, reduced dendritic spine density, increased hyperpolarization-activated cation currents and alterations in social behavior. Given previous evidence showing that WNT signaling is Tbr1-dependent and the identification of WNT-related transcripts as Tbr1 targets, Rubenstein and colleagues then asked whether restoring normal WNT signaling could rescue any of these phenotypes. Strikingly, administration of LiCl or a GSK3b inhibitor, both expected to normalize WNT signaling, had substantial effects on synapse and dendritic spine development in deep-layer pyramidal neurons, as well as on social behavior.

The authors proposed a model for Tbr1 function in deep-layer neurons that includes its regulation of WNT signaling, retinoic acid metabolism and kinesin-dependent transport. They concluded by suggesting that LiCl should be rigorously evaluated as a possible therapy for Tbr1-associated syndrome as well as for conditions with overlapping synaptic abnormalities.