Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
European Archives of Psychiatry and Clinical Neuroscience
Published in: European Archives of Psychiatry and Clinical Neuroscience 6/2016

01-09-2016 | Original Paper

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

Authors: M. M. Brzózka, M. J. Rossner, L. de Hoz

Published in: European Archives of Psychiatry and Clinical Neuroscience | Issue 6/2016

Login to get access

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.
Literature
1.
2.
3.
Tamminga CA, Holcomb HH (2005) Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 10(1):27–39CrossRefPubMed
4.
Gray NS, Pickering AD, Hemsley DR, Dawling S, Gray JA (1992) Abolition of latent inhibition by a single 5 mg dose of d-amphetamine in man. Psychopharmacology 107(2–3):425–430CrossRefPubMed
5.
Vaitl D, Lipp OV (1997) Latent inhibition and autonomic responses: a psychophysiological approach. Behav Brain Res 88(1):85–93CrossRefPubMed
6.
Rascle C, Mazas O, Vaiva G, Tournant M, Raybois O, Goudemand M et al (2001) Clinical features of latent inhibition in schizophrenia. Schizophr Res 51(2–3):149–161CrossRefPubMed
7.
Vaitl D, Lipp O, Bauer U, Schüler G, Stark R, Zimmermann M et al (2002) Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses. Schizophr Res 55(1–2):147–158CrossRefPubMed
8.
Weiner I, Arad M (2009) Using the pharmacology of latent inhibition to model domains of pathology in schizophrenia and their treatment. Behav Brain Res 204(2):369–386CrossRefPubMed
9.
Lubow RE, Moore AU (1959) Latent inhibition: the effect of nonreinforced pre-exposure to the conditional stimulus. J Comp Physiol Psychol. 52:415–419CrossRefPubMed
10.
Meyer F, Louilot A (2014) Consequences at adulthood of transient inactivation of the parahippocampal and prefrontal regions during early development: new insights from a disconnection animal model for schizophrenia. Front Behav Neurosci 7:118CrossRefPubMed
11.
Moser PC, Hitchcock JM, Lister S, Moran PM (2000) The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Brain Res Rev 33(2–3):275–307CrossRefPubMed
12.
Weiner I (2003) The, “two-headed” latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment. Psychopharmacology 169(3–4):257–297CrossRefPubMed
13.
Labrie V, Lipina T, Roder JC (2008) Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology 200(2):217–230CrossRefPubMed
14.
Lubow RE (2005) Construct validity of the animal latent inhibition model of selective attention deficits in schizophrenia. Schizophr Bull 31(1):139–153CrossRefPubMed
15.
Lubow RE, Gewirtz JC (1995) Latent inhibition in humans: data, theory, and implications for schizophrenia. Psychol Bull 117(1):87–103CrossRefPubMed
16.
Weiner I, Schnabel I, Lubow RE, Feldon J (1985) The effects of early handling on latent inhibition in male and female rats. Dev Psychobiol 18(4):291–297CrossRefPubMed
17.
Swerdlow NR, Braff DL, Hartston H, Perry W, Geyer MA (1996) Latent inhibition in schizophrenia. Schizophr Res 20(1–2):91–103CrossRefPubMed
18.
Williams JH, Wellman NA, Geaney DP, Cowen PJ, Feldon J, Rawlins JN (1998) Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment. Br J Psychiatry J Ment Sci 172:243–249CrossRef
19.
20.
Solomon PR, Crider A, Winkelman JW, Turi A, Kamer RM, Kaplan LJ (1981) Disrupted latent inhibition in the rat with chronic amphetamine or haloperidol-induced supersensitivity: relationship to schizophrenic attention disorder. Biol Psychiatry 16(6):519–537PubMed
21.
Weiner I, Lubow RE, Feldon J (1984) Abolition of the expression but not the acquisition of latent inhibition by chronic amphetamine in rats. Psychopharmacology 83(2):194–199CrossRefPubMed
22.
Weiner I, Lubow RE, Feldon J (1988) Disruption of latent inhibition by acute administration of low doses of amphetamine. Pharmacol Biochem Behav 30(4):871–878CrossRefPubMed
23.
McGue M, Gottesman II (1991) The genetic epidemiology of schizophrenia and the design of linkage studies. Eur Arch Psychiatry Clin Neurosci 240(3):174–181CrossRefPubMed
24.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al (2009) Common variants conferring risk of schizophrenia. Nature 460(7256):744–747PubMedPubMedCentral
25.
Li T, Li Z, Chen P, Zhao Q, Wang T, Huang K et al (2010) Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese. Biol Psychiatry 68(7):671–673CrossRefPubMed
26.
Steinberg S, de Jong S, Irish Schizophrenia Genomics Consortium, Andreassen OA, Werge T, Børglum AD et al (2011) Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum Mol Genet 20(20):4076–4081CrossRefPubMedPubMedCentral
27.
Schizophrenia Psychiatric Genome-Wide Association Study (2011) (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43(10):969–976CrossRef
28.
Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2 (2012) Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry 72(8):620–628CrossRefPubMedCentral
29.
Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159CrossRefPubMedPubMedCentral
30.
Wirgenes KV, Sønderby IE, Haukvik UK, Mattingsdal M, Tesli M, Athanasiu L et al (2012) TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Transl Psychiatry 2:e112CrossRefPubMedPubMedCentral
31.
Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473(7346):221–225CrossRefPubMedPubMedCentral
32.
Guella I, Sequeira A, Rollins B, Morgan L, Torri F, van Erp TGM et al (2013) Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. J Psychiatr Res 47(9):1215–1221CrossRefPubMedPubMedCentral
33.
Umeda-Yano S, Hashimoto R, Yamamori H, Weickert CS, Yasuda Y, Ohi K et al (2014) Expression analysis of the genes identified in GWAS of the postmortem brain tissues from patients with schizophrenia. Neurosci Lett 7(568):12–16CrossRef
34.
Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N et al (2007) Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet 80(5):988–993CrossRefPubMedPubMedCentral
35.
Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton-Smith J et al (2007) Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt–Hopkins syndrome). Am J Hum Genet 80(5):994–1001CrossRefPubMedPubMedCentral
36.
de Pontual L, Mathieu Y, Golzio C, Rio M, Malan V, Boddaert N et al (2009) Mutational, functional, and expression studies of the TCF4 gene in Pitt–Hopkins syndrome. Hum Mutat 30(4):669–676CrossRefPubMed
37.
Forrest M, Chapman RM, Doyle AM, Tinsley CL, Waite A, Blake DJ (2012) Functional analysis of TCF4 missense mutations that cause Pitt–Hopkins syndrome. Hum Mutat 33(12):1676–1686CrossRefPubMed
38.
39.
Soosaar A, Chiaramello A, Zuber MX, Neuman T (1994) Expression of basic-helix-loop-helix transcription factor ME2 during brain development and in the regions of neuronal plasticity in the adult brain. Brain Res Mol Brain Res 25(1–2):176–180CrossRefPubMed
40.
Chiaramello A, Soosaar A, Neuman T, Zuber MX (1995) Differential expression and distinct DNA-binding specificity of ME1a and ME2 suggest a unique role during differentiation and neuronal plasticity. Brain Res Mol Brain Res 29(1):107–118CrossRefPubMed
41.
Brzózka MM, Radyushkin K, Wichert SP, Ehrenreich H, Rossner MJ (2010) Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain. Biol Psychiatry 68(1):33–40CrossRefPubMed
42.
Flora A, Garcia JJ, Thaller C, Zoghbi HY (2007) The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc Natl Acad Sci USA 104(39):15382–15387CrossRefPubMedPubMedCentral
43.
Zhuang Y, Cheng P, Weintraub H (1996) B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol Cell Biol 16(6):2898–2905CrossRefPubMedPubMedCentral
44.
45.
Brzózka MM, Rossner MJ (2013) Deficits in trace fear memory in a mouse model of the schizophrenia risk gene TCF4. Behav Brain Res 15(237):348–356CrossRef
46.
Quednow BB, Brzózka MM, Rossner MJ (2014) Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cell Mol Life Sci CMLS 71(15):2815–2835CrossRefPubMed
47.
Falkai P, Rossner MJ, Schulze TG, Hasan A, Brzózka MM, Malchow B et al (2015) Kraepelin revisited: schizophrenia from degeneration to failed regeneration. Mol Psychiatry 20(6):671–676CrossRefPubMed
48.
49.
50.
Morice R (1990) Cognitive inflexibility and pre-frontal dysfunction in schizophrenia and mania. Br J Psychiatry J Ment Sci 157:50–54CrossRef
51.
Floresco SB, Zhang Y, Enomoto T (2009) Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav Brain Res 204(2):396–409CrossRefPubMed
52.
Levin HS, Eisenberg HM, Benton AL (1991) Frontal lobe function and dysfunction. Oxford University Press, Oxford, p 458
53.
54.
Schiller D, Weiner I (2004) Lesions to the basolateral amygdala and the orbitofrontal cortex but not to the medial prefrontal cortex produce an abnormally persistent latent inhibition in rats. Neuroscience 128(1):15–25CrossRefPubMed
55.
Lipska BK, Swerdlow NR, Geyer MA, Jaskiw GE, Braff DL, Weinberger DR (1995) Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology 122(1):35–43CrossRefPubMed
56.
Grecksch G, Bernstein HG, Becker A, Höllt V, Bogerts B (1999) Disruption of latent inhibition in rats with postnatal hippocampal lesions. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 20(6):525–532CrossRef
57.
Feldon J, Avnimelech-Gigus N, Weiner I (1990) The effects of pre- and post-weaning rearing conditions on latent inhibition and partial reinforcement extinction effect in male rats. Behav Neural Biol 53(2):189–204CrossRefPubMed
58.
Shalev U, Feldon J, Weiner I (1998) Gender- and age-dependent differences in latent inhibition following pre-weaning non-handling: implications for a neurodevelopmental animal model of schizophrenia. Int J Dev Neurosci Off J Int Soc Dev Neurosci 16(3–4):279–288CrossRef
59.
Bethus I, Lemaire V, Lhomme M, Goodall G (2005) Does prenatal stress affect latent inhibition? It depends on the gender. Behav Brain Res 158(2):331–338CrossRefPubMed
60.
Quinlan MG, Duncan A, Loiselle C, Graffe N, Brake WG (2010) Latent inhibition is affected by phase of estrous cycle in female rats. Brain Cogn 74(3):244–248CrossRefPubMed
Metadata
Title
Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm
Authors
M. M. Brzózka
M. J. Rossner
L. de Hoz
Publication date
01-09-2016
Publisher
Springer Berlin Heidelberg
Published in
European Archives of Psychiatry and Clinical Neuroscience / Issue 6/2016
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI
https://doi.org/10.1007/s00406-015-0643-8

Other articles of this Issue 6/2016

European Archives of Psychiatry and Clinical Neuroscience 6/2016 Go to the issue

Editorial

Network meta-analyses should be the highest level of evidence in treatment guidelines

Original Paper

Relationship between hippocampal subfield volumes and memory deficits in patients with thalamus infarction

Original Paper

Neural systems for social cognition: gray matter volume abnormalities in boys at high genetic risk of autism symptoms, and a comparison with idiopathic autism spectrum disorder

Original Paper

Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia

Original Paper

The SWITCH study: rationale and design of the trial

Editorial

Stepping up: the just released new impact factor 2015