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 m...

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Bibliographic Details
Published in:Neurobiology of aging 2017-01, Vol.49, p.40-51
Main Authors: Soler, H, Dorca-Arévalo, J, González, M, Rubio, S.E, Avila, J, Soriano, E, Pascual, M
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer Disease - physiopathology
Alzheimer Disease - psychology
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Animals
Disease Models, Animal
GABAergic Neurons - metabolism
GABAergic Neurons - physiology
Hippocampal interneurons
Hippocampus - physiopathology
Hyperphosphorylated Tau
Internal Medicine
Learning
Male
Memory
Mice, Inbred C57BL
Mutation
Neurology
Parvalbumin-positive cells
Phosphorylation
Protein Aggregation, Pathological
Septum of Brain - physiopathology
tau Proteins - genetics
tau Proteins - metabolism
Tauopathies - metabolism
Tauopathies - physiopathology
Tauopathies - psychology
VLW mice
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Summary: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 ( Rubio et al., 2012 ). 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 (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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2016.09.006