Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm

Eur Arch Psychiatry Clin Neurosci. 2016 Sep;266(6):505-12. doi: 10.1007/s00406-015-0643-8. Epub 2015 Sep 24.


Schizophrenia (SZ) is a severe mental disorder affecting about 1 % of the human population. Patients show severe deficits in cognitive processing often characterized by an improper filtering of environmental stimuli. Independent genome-wide association studies confirmed a number of risk variants for SZ including several associated with the gene encoding the transcription factor 4 (TCF4). TCF4 is widely expressed in the central nervous system of mice and humans and seems to be important for brain development. Transgenic mice overexpressing murine Tcf4 (Tcf4tg) in the adult brain display cognitive impairments and sensorimotor gating disturbances. To address the question of whether increased Tcf4 gene dosage may affect cognitive flexibility in an auditory associative task, we tested latent inhibition (LI) in female Tcf4tg mice. LI is a widely accepted translational endophenotype of SZ and results from a maladaptive delay in switching a response to a previously unconditioned stimulus when this becomes conditioned. Using an Audiobox, we pre-exposed Tcf4tg mice and their wild-type littermates to either a 3- or a 12-kHz tone before conditioning them to a 12-kHz tone. Tcf4tg animals pre-exposed to a 12-kHz tone showed significantly delayed conditioning when the previously unconditioned tone became associated with an air puff. These results support findings that associate TCF4 dysfunction with cognitive inflexibility and improper filtering of sensory stimuli observed in SZ patients.

Keywords: Behavioral flexibility; Latent inhibition; Schizophrenia; Tcf4.

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Cognition Disorders / genetics*
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Female
  • General Adaptation Syndrome / genetics*
  • Inhibition, Psychological
  • Locomotion / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Psychoacoustics
  • Sensory Gating / genetics*
  • Transcription Factor 4


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Tcf4 protein, mouse
  • Transcription Factor 4