Summary: Chemically activating neurons and placing mice in stimulating environments reverses alterations and restores some neural connectivity in frontotemporal dementia. If translated into humans, the findings could help develop new treatments for fighting the effects of dementia in the elderly.
Dysfunctional neurons in the hippocampus of adult female mice modeling dementia can be repaired and reconnected to distant parts of the brain, reports a new study published in Journal of Neuroscience. The similarity between the mouse model and the human condition underscores the therapeutic potential of targeting these cells in dementia patients.
The hippocampus generates new brain cells throughout life and is implicated in neurodegenerative diseases. María Llorens-Martín and colleagues at the Centro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM) used a mouse model of frontotemporal dementia to investigate the effects of the disease on dentate granule cells.
Compared to control subjects, the researchers observed strikingly similar alterations in newborn neurons from their mouse model and from human brain tissue of patients with frontotemporal dementia. In mice, chemically activating the cells and placing animals in a stimulating environment with running wheels and toys reversed the alterations and restore some of the connectivity disrupted by dementia. If translated to humans, these results suggest potential new directions for combating cognitive decline in the elderly.
About this neuroscience research article
Source: SfN Media Contacts: David Barnstone – SfN Image Source: The image is credited to Terreros-Roncal et al. JNeurosci (2019).
Activity-dependent reconnection of adult-born dentate granule cells in a mouse model of frontotemporal dementia
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, namely TauVLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout 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 Synaptophysin: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 pre- and post-synaptic markers of inhibitory synapses was markedly increased in the DG of TauVLW mice and FTD patients. Moreover, an increased number of NeuropeptideY+ 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 TauVLM mice and FTD patients.
In the present manuscript, we show, for the first time, that the population of dentate granule cells is disconnected from other regions of the brain in a neurodegenerative disease called 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, namely 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.