Modulation ofTcf7l2 expression alters behavior in mice.

The comorbidity of type 2 diabetes (T2D) with several psychiatric diseases is well established. While environmental factors may partially account for these co-occurrences, common genetic susceptibilities could also be implicated in the confluence of these diseases. In support of shared genetic burdens, TCF7L2, the strongest genetic determinant for T2D risk in the human population, has been recently implicated in schizophrenia (SCZ) risk, suggesting that this may be one of many loci that pleiotropically influence both diseases. To investigate whether Tcf7l2 is involved in behavioral phenotypes in addition to its roles in glucose metabolism, we conducted several behavioral tests in mice with null alleles of Tcf7l2 or overexpressing Tcf7l2. We identified a role for Tcf7l2 in anxiety-like behavior and a dose-dependent effect of Tcf7l2 alleles on fear learning. None of the mutant mice showed differences in prepulse inhibition (PPI), which is a well-established endophenotype for SCZ. These results show that Tcf7l2 alters behavior in mice. Importantly, these differences are observed prior to the onset of detectable glucose metabolism abnormalities. Whether these differences are related to human anxiety-disorders or schizophrenia remains to be determined. These animal models have the potential to elucidate the molecular basis of psychiatric comorbidities in diabetes and should therefore be studied further.