Activity‐dependent reconnection of adult‐born dentate granule cells in a mouse model of frontotemporal dementia

Background Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by a loss of neurons in the frontal and temporal lobes of the brain. Tau protein is encoded by MAPT gene and its mutations cause FTD‐Tau, FTD variant. TauVLW mice carries three mutations, G272V (V), P301L (L), and R406W (W) on MAPT, increasing the susceptibility of Tau to be phosphorylated. TauVLW mice show anatomical alterations in the hippocampus as well as behavioural impairments. Importantly, the hippocampus gives rise to new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), converges in the functional integration of mature dentate granule cells (DGCs) into the trisynaptic hippocampal circuit. AHN is altered in patients with Alzheimer´s disease and in animal models of distinct neurodegenerative diseases, including FTD. Methods To perform an in‐depth characterization of newborn DGCs of TauVLW mice we used a combination of trail‐blazing retroviral approaches. We used Red‐Green‐Blue (RGB) retroviruses to address the morphological maturation of these neurons. We also used retroviruses that encode either PSD95:GFP or Synaptophysin (Syn):GFP, together with monosynaptic retrograde rabies virus tracing to study the connectivity of these cells. Finally, we tested the effects of the selective chemoactivation of newborn DGCs using a retrovirus that encodes the excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) H3Dmq, as modulator to counteract the alterations. Results These innovative approaches revealed that the newborn DGCs of TauVLW mice exhibit marked morphological and functional alterations. Importantly, similar morphological alterations are observed in DGCs of FTD patients. Newborn DGCs of TauVLW mice show impaired afferent and efferent connectivity. Moreover, they are disconnected from distal brain regions and exhibited a predominance of local inhibitory innervation. Therefore, a reduced number of activated egr‐1 + DGCs were observed. On the other hand, chemoactivation led to a complete reversal of the morphological alterations and partial reversal of the alterations in the connectivity of these cells. Conclusions DGCs are disconnected from distal brain regions and local sources of excitatory innervation in a mouse model of FTD. These cells exhibit remarkable similarities with those of FTD patients. Significantly, the functional defects observed in TauVLW newborn DGCs are reversed by chemoactivation.