Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a Mouse Model of Frontotemporal Dementia
| Autor: | Alejandro F. Schinder, Miguel Flor-García, Damiana Giacomini, María Llorens-Martín, Alberto Rábano, Elena P. Moreno-Jiménez, Nirnath Sah, Jesús Avila, Henriette van Praag, Julia Terreros-Roncal, Noemí Pallas-Bazarra |
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| Přispěvatelé: | Association for Frontotemporal Degeneration (US), Comunidad de Madrid, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Howard Hughes Medical Institute, National Institute on Aging (US), Fundación Ramón Areces, Banco Santander, Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Neurogenesis Population purl.org/becyt/ford/3.5 [https] Mice Transgenic Biology Hippocampal formation Inhibitory postsynaptic potential Mice 03 medical and health sciences 0302 clinical medicine Postsynaptic potential mental disorders medicine Animals Humans education Research Articles ENVIRONMENTAL ENRICHMENT Environmental enrichment education.field_of_study General Neuroscience Dentate gyrus RGB RETROVIRUS Age Factors RABIES VIRUS medicine.disease FRONTOTEMPORAL DEMENTIA (FTD) Mice Inbred C57BL Disease Models Animal 030104 developmental biology Frontotemporal Dementia Dentate Gyrus DREADD Excitatory postsynaptic potential Female purl.org/becyt/ford/3 [https] Neuroscience DENTATE GRANULE CELLS (DGCS) 030217 neurology & neurosurgery Frontotemporal dementia |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, TauVLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female TauVLW mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn TauVLW DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of TauVLW mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1+ DGCs in TauVLW mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of TauVLW mice and FTD patients.SIGNIFICANCE STATEMENT We show, for the first time to our knowledge, that the population of dentate granule cells is disconnected from other regions of the brain in the neurodegenerative disease frontotemporal dementia (FTD). These alterations were observed in FTD patients and in a mouse model of this disease. Moreover, we tested the therapeutic potential of two strategies, environmental enrichment and chemoactivation, to stimulate the activity of these neurons in mice. We found that some of the alterations were reversed by these therapeutic interventions. Association for Frontotemporal Degeneration (2016 Basic Science Pilot Grant Award to M.L.-M.); the Comunidad de Madrid (PEJD-2017-PRE/BMD-3439 to M.L.-M.); the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED to J.A.); the Argentine Agency for the Promotion of Science and Technology (PICT2015-3814 and PICT2013-1685 to A.S.); the Howard Hughes Medical Institute (SIRS Grant 55007652 to A. S.); and the National Institute on Aging (Intramural Research Program to H.v.P.). Institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO; the Spanish Ministry of Economy and Competitiveness (SAF-2017-82185-R |
| Databáze: | OpenAIRE |
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