title: Transient downregulation of Dab1 protein levels during development leads to behavioral and structural deficits: relevance for psychiatric disorders.
abstract: Psychiatric disorders have been hypothesized to originate during development, with genetic and environmental factors interacting in the etiology of disease. Therefore, developmentally regulated genes have received attention as risk modulators in psychiatric diseases. Reelin is an extracellular protein essential for neuronal migration and maturation during development, and its expression levels are reduced in psychiatric disorders. Interestingly, several perinatal insults that increase the risk of behavioral deficits alter Reelin signaling. However, it is not known whether a dysfunction in Reelin signaling during perinatal stages increases the risk of psychiatric disorders. Here we used a floxed dab1 allele to study whether a transient decrease in Dab1, a key component of the Reelin pathway, is sufficient to induce behavioral deficits related to psychiatric disorders. We found that transient Dab1 downregulation during perinatal stages leads to permanent abnormalities of structural layering in the neocortex and hippocampus. In contrast, conditional inactivation of the dab1 gene in the adult brain does not result in additional layering abnormalities. Furthermore, perinatal Dab1 downregulation causes behavior impairments in adult mice, such as deficits in memory, maternal care, pre-pulse inhibition, and response to cocaine. Some of these deficits were also found to be present in adolescence. We also show that D-cycloserine rescues the cognitive deficits observed in floxed dab1 mice with layering alterations in the hippocampus and neocortex. Our results indicate a causal relation between the downregulation of Dab1 protein levels during development and the structural and behavioral deficits associated with psychiatric diseases in the adult.
authors.affiliation: 1] Department of Cell Biology, University of Barcelona, Barcelona, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: Catia M
authors.initials: CM
authors.lastname: Teixeira
authors.affiliation: 1] Department of Cell Biology, University of Barcelona, Barcelona, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Masachs
authors.affiliation: 1] Department of Cell Biology, University of Barcelona, Barcelona, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Muhaisen
authors.affiliation: 1] Department of Cell Biology, University of Barcelona, Barcelona, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Bosch
authors.affiliation: Institute of Neurosciences, CSIC and Miguel Hernández University, Alicante, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez-Martínez
authors.affiliation: Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Howell
authors.affiliation: 1] Department of Cell Biology, University of Barcelona, Barcelona, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain [3] Fundación CIEN, Vallecas, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D003345:Corticosterone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D013629:Tamoxifen / Q000494:pharmacology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C103773:Dab1 protein, mouse; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D013629:Tamoxifen; D001616:beta-Galactosidase; C000717128:Reln protein, mouse; D003024:Clozapine; D003345:Corticosterone
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