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Barcelona, Spain

Mellstrom B.,CSIC - National Center for Biotechnology | Sahun I.,Genomic Regulation Center | Ruiz-Nuno A.,University of Birmingham | Murtra P.,University Pompeu Fabra | And 17 more authors.
Molecular and Cellular Biology | Year: 2014

Changes in nuclear Ca2+ homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K+ channel interacting protein 3), is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activitydependent gene expression programs that control synaptic plasticity, learning, and memory. © 2014, American Society for Microbiology.

Souchet B.,University Paris Diderot | Guedj F.,University Paris Diderot | Sahun I.,Genomic Regulation Center | Sahun I.,Research Center Biomedica En Red Of Enfermedades Raras | And 14 more authors.
Neurobiology of Disease | Year: 2014

Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations. © 2014 Elsevier Inc.

Dierssen M.,Genomic Regulation Center | Fedrizzi L.,University of Padua | Gomez-Villafuertes R.,Research Center Biomedica en Red | de Lagran M.M.,Genomic Regulation Center | And 8 more authors.
Frontiers in Molecular Neuroscience | Year: 2012

Downstream regulatory element antagonist modulator (DREAM) is a C a2+-binding protein that binds DNA and represses transcription in a Ca 2+-dependent manner. Previous work has shown a role for DREAM in cerebellar function regulating the expression of the sodium/calcium exchanger 3 (NCX3) in cerebellar granular neurons to control Ca 2+ homeostasis and survival of these neurons. To achieve a global view of the genes regulated by DREAM in the cerebellum, we performed a genome-wide analysis in transgenic cerebellum expressing a Ca 2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Here we show that DREAM regulates the expression of the midline 1 (Mid1) gene early after birth. As a consequence, daDREAM mice exhibit a significant shortening of the rostro-caudal axis of the cerebellum and a delay in neuromotor development early after birth. Our results indicate a role for DREAM in cerebellar function. © 2012 Dierssen, Fedrizzi, Gomez-Villafuertes, de Lagran, Gutierrez-Adan, Sahún, Pintado, Oliveros, Dopazo, Gonzalez, Brini, Mellström, Carafoli and Naranjo.

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