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Free keywords:
PITT-HOPKINS-SYNDROME; TRANSCRIPTION FACTOR; INTELLECTUAL DISABILITY;
MENTAL-RETARDATION; ANIMAL-MODELS; MEMORY; ENVIRONMENT; EXPRESSION;
MUTATIONS; STRESSPsychiatry;
Abstract:
The transcription factorTCF4was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressingTcf4in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposedTcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4 delta(+/-)) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits ofTcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression inTcf4tg mice and enhanced long-term potentiation inTcf4Ex4 delta(+/-)mice indicating specific gene-dosage effects.Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.
