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

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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.

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Acknowledgments

This study was supported by KFO241 (Klinische Forschergruppe 241) Grants RO 4076/1-1 and RO 4076/5-1 to M.J.R and M.M.B.

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Authors and Affiliations

  1. Molecular and Behavioral Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, 80336, Munich, Germany

    M. M. Brzózka & M. J. Rossner

  2. Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany

    M. J. Rossner & L. de Hoz

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  1. M. M. Brzózka
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  2. M. J. Rossner
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  3. L. de Hoz
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Correspondence to M. J. Rossner or L. de Hoz.

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Brzózka, M.M., Rossner, M.J. & de Hoz, L. Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm. Eur Arch Psychiatry Clin Neurosci 266, 505–512 (2016). https://doi.org/10.1007/s00406-015-0643-8

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