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The transcription factor  TCF4  was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing  Tcf4  in forebrain ( Tcf4 tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed  Tcf4 tg 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 ( Tcf4Ex4δ   +/−  ) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of  Tcf4 tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in  Tcf4 tg mice and enhanced long-term potentiation in  Tcf4Ex4δ   +/−   mice indicating specific gene-dosage effects.  Tcf4 tg 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.

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