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

Abstract

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.

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

“…In animal models, it was demonstrated that overexpression of TCF4 in mice resulted in sensorimotor and fear conditioning impairments, highlighting the relevance of TCF4 in cognitive processes (Brzózka et al, 2010, 2016; Brzózka & Rossner, 2013). Analysis of Tcf4 polymorphisms in humans with schizophrenia confirmed the influence of this TF in processes like verbal declarative memory (Lennertz et al, 2011), attention‐related tasks (Zhu et al, 2013), problem‐solving tasks (Albanna et al, 2014), and lower cognitive performance (Hui et al, 2015).…”

Modulation of cognition and neuronal plasticity in gain- and loss-of-function mouse models of the schizophrenia risk gene Tcf4

“…TCF4 transcript levels have been shown to be moderately increased in blood cells of SZ patients and in neurons derived from induced pluripotent stem cells (IPSCs) 17,18 as well as in postmortem brain tissue of SZ patients 19,20 . Moreover, transgenic mice that slightly overexpress a long Tcf4 variant (corresponding to the TCF4B variant as described by Sepp et al 3 in the cortex and hippocampus (Tcf4tg mice) display deficits in sensory gating and impairments in fear-associated learning, attentional dysfunction, and delayed adaptation in a latent inhibition task [21][22][23] . TCF4 is considered a constitutive interaction partner of neuronal bHLH factors and displays pleiotrophic effects 1 and has been shown to be regulated post-trancriptionally by neuronal activity 24 .…”

Effects of LncRNA GAS5/miR-137 general anesthesia on cognitive function by TCF4 inflammatory bodies in patients undergoing lumbar spinal canal decompression

“…[ 37 ] According to recent research, the role of TCF4 in central nervous system diseases has become a hot topic receiving general attention, which exerts an important function in the neuronal regulation. [ 38 , 39 ] In the present study, LncRNA GAS5 induced TCF4 protein expression in vitro model by miR-137. Transcription factor TCF4 activates the expression of bHLH.…”