ABSTRACT
Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.
Subject(s)
Extinction, Psychological/physiology , Fear/physiology , Gene Expression Regulation , Hippocampus/metabolism , Insulin-Like Growth Factor II/metabolism , Memory/physiology , Animals , Animals, Newborn , Cell Proliferation , Insulin-Like Growth Factor Binding Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Biological , Neurons/metabolism , Oligonucleotide Array Sequence Analysis , Signal Transduction , Time FactorsABSTRACT
Increasing evidence suggests an important function of the ß-amyloid precursor protein (APP) in malignant disease in humans; however, the biological basis for this evidence is not well understood at present. To understand the role of APP in transformed pluripotent stem cells, we studied its expression levels in human testicular germ cell tumors using patient tissues, model cell lines, and an established xenograft mouse model. In the present study, we demonstrate the cooperative expression of APP with prominent pluripotency-related genes such as Sox2, NANOG, and POU5F1 (Oct3/4). The closest homologue family member, APLP2, showed no correlation to these stem cell factors. In addition, treatment with histone deacetylase (HDAC) inhibitors suppressed the levels of APP and stem cell markers. Loss of pluripotency, either spontaneously or as a consequence of treatment with an HDAC inhibitor, was accompanied by decreased APP protein levels both in vitro and in vivo. These observations suggest that APP represents a novel and specific biomarker in human transformed pluripotent stem cells that can be selectively modulated by HDAC inhibitors.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Biomarkers, Tumor/metabolism , Neoplasms, Germ Cell and Embryonal/metabolism , Pluripotent Stem Cells/metabolism , Testicular Neoplasms/metabolism , Adolescent , Adult , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/pharmacology , Animals , Biomarkers, Tumor/genetics , Cell Differentiation/drug effects , Cell Transformation, Neoplastic/metabolism , Endoplasmic Reticulum Chaperone BiP , Heat-Shock Proteins/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Humans , Male , Mice , Mice, Nude , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/pathology , Protein Processing, Post-Translational/drug effects , Recombinant Proteins/pharmacology , Testicular Neoplasms/drug therapy , Testicular Neoplasms/pathology , Transcription, Genetic/drug effects , Tumor Cells, Cultured , Valproic Acid/pharmacology , Valproic Acid/therapeutic use , Xenograft Model Antitumor Assays , Young AdultABSTRACT
As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.