Cognitive and Sensorimotor Gating Impairments in Transgenic Mice Overexpressing the Schizophrenia Susceptibility Gene Tcf4 in the Brain

Abstract

The combined analysis of several large genome-wide association studies identified the basic helix-loop-helix (bHLH) transcription factor TCF4 as one of the most significant schizophrenia susceptibility genes. Its function in the adult brain, however, is not known. TCF4 belongs to the E-protein subfamily known to be involved in neurodevelopment. The messenger RNA expression of Tcf4 is sustained in the adult mouse brain, suggesting a function in the adult nervous system. Tcf4 null mutant mice die perinatally, and haploinsufficiency of TCF4 in humans causes severe mental retardation. To investigate the possible function of TCF4 in the adult central nervous system, we generated transgenic mice that moderately overexpress TCF4 postnatally in the brain to reduce the risk of developmental effects possibly interfering with adult brain functions. Tcf4 transgenic mice were characterized with molecular, histological, and behavioral methods. Tcf4 transgenic mice display profound deficits in contextual and cued fear conditioning and sensorimotor gating. Furthermore, we show that TCF4 interacts with the neurogenic bHLH factors NEUROD and NDRF in vivo. Molecular analyses revealed the dynamic circadian deregulation of neuronal bHLH factors in the adult hippocampus. We conclude that TCF4 likely acts in concert with other neuronal bHLH transcription factors contributing to higher-order cognitive processing. Moderate transcriptional deregulation of Tcf4 in the brain interferes with cognitive functions and might alter circadian processes in mice. These observations provide insight for the first time into the physiological function of TCF4 in the adult brain and its possible contributions to neuropsychiatric disease conditions.