RT Journal Article
SR Electronic
T1 Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a Mouse Model of Frontotemporal Dementia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5794
OP 5815
DO 10.1523/JNEUROSCI.2724-18.2019
VO 39
IS 29
A1 Julia Terreros-Roncal
A1 Miguel Flor-García
A1 Elena P. Moreno-Jiménez
A1 Noemí Pallas-Bazarra
A1 Alberto Rábano
A1 Nirnath Sah
A1 Henriette van Praag
A1 Damiana Giacomini
A1 Alejandro F. Schinder
A1 Jesús Ávila
A1 Maria Llorens-Martín
YR 2019
UL http://www.jneurosci.org/content/39/29/5794.abstract
AB 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.