INTRODUCTION: TCF7L2 is a transcriptional effector of the Wnt/β-catenin signaling pathway, which controls developmental and homeostatic processes and is a risk gene for autism spectrum disorder (ASD). TCF7L2 is expressed in the thalamus, where it regulates the establishment of thalamocortical connections and electrophysiological maturation of neurons. The role of TCF7L2 in regulating behavioural profiles has not been fully investigated.

AIM(S): We hypothesized that postnatal thalamus-specific deficiency of TCF7L2 impairs thalamocortical circuits and leads to autism-like behaviours.

METHOD(S): We investigated these hypotheses using mice with Tcf7l2 knockout mediated by Cre recombinase, whose expression was induced postnatally in thalamic neurons. We analyzed the behavioural profile of the conditional Tcf7l2 knockout (Tcf7l2 cKO) mice to assess social performance through Eco-HAB, Three-chamber, and Investigative interaction tests.

RESULTS: Tcf7l2 cKO presented a decrease in social interest, not interacting with other mice during the chamber exploration, spending less time near the social scent, and a decreased number of social contacts, demonstrating that the deletion of Tcf7l2 affects conspecific social cue recognition. After six weeks of ketogenic diet intervention, the majority of social parameters were rescued in cKO mice.

CONCLUSIONS: These results corroborate a hypothesis that thalamic dysfunctions originating from perinatal development can be a primary cause of social deficits. The response to the ketogenic diet suggests that impaired energy metabolism in thalamocortical circuits plays a role in the pathogenesis of ASD.

FINANCIAL SUPPORT: Financial support: Narodowe Centrum Nauki (NCN, National Science Center) grant 2020/37/B/NZ4/03261