title: The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy.
abstract: Alzheimer's disease (AD), the most common cause of dementia nowadays, has been linked to alterations in the septohippocampal pathway (SHP), among other circuits in the brain. In fact, the GABAergic component of the SHP, which controls hippocampal rhythmic activity crucial for learning and memory, is altered in the J20 mouse model of AD-a model that mimics the amyloid pathology of this disease. However, AD is characterized by another pathophysiological hallmark: the hyperphosphorylation and aggregation of the microtubule-associated protein Tau. To evaluate whether tauopathies alter the GABAergic SHP, we analyzed transgenic mice expressing human mutated Tau (mutations G272V, P301L, and R406W, VLW transgenic strain). We show that pyramidal neurons, mossy cells, and some parvalbumin (PARV)-positive hippocampal interneurons in 2- and 8-month-old (mo) VLW mice accumulate phosphorylated forms of Tau (P-Tau). By tract-tracing studies of the GABAergic SHP, we describe early-onset deterioration of GABAergic septohippocampal (SH) innervation on PARV-positive interneurons in 2-mo VLW mice. In 8-mo animals, this alteration was more severe and affected mainly P-Tau-accumulating PARV-positive interneurons. No major loss of GABAergic SHP neurons or PARV-positive hippocampal interneurons was observed, thereby indicating that this decline is not caused by neuronal loss but by the reduced number and complexity of GABAergic SHP axon terminals. The decrease in GABAergic SHP described in this study, targeted onto the PARV-positive/P-Tau-accumulating inhibitory neurons in the hippocampus, establishes a cellular correlation with the dysfunctions in rhythmic neuronal activity and excitation levels in the hippocampus. These dysfunctions are associated with the VLW transgenic strain in particular and with AD human pathology in general. These data, together with our previous results in the J20 mouse model, indicate that the GABAergic SHP is impaired in response to both amyloid-β and P-Tau accumulation. We propose that alterations in the GABAergic SHP, together with a dysfunction of P-Tau-accumulating PARV-positive neurons, contribute to the cognitive deficits and altered patterns of hippocampal activity present in tauopathies, including AD.
authors.affiliation: Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Soler
authors.affiliation: Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Dorca-Arévalo
authors.affiliation: Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: González
authors.affiliation: Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: Sara Esmeralda
authors.initials: SE
authors.lastname: Rubio
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain; Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Neurobiology Laboratory, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ávila
authors.affiliation: Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats Academia, Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
authors.affiliation: Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain. Electronic address: marpascual@ub.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Pascual
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000378:metabolism* / Q000502:physiology*; D006624:Hippocampus / Q000503:physiopathology*; D007858:Learning; D008297:Male; D008568:Memory; D008810:Mice, Inbred C57BL; D009154:Mutation; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological; D020665:Septum of Brain / Q000503:physiopathology*; D024801:Tauopathies / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins
keywords: Alzheimer's disease; Hippocampal interneurons; Hyperphosphorylated Tau; Parvalbumin-positive cells; VLW mice