Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs

• Published in: Experimental neurology Vol. 223; no. 2; pp. 385 - 393
• Main Authors: Rocher, A.B., Crimins, J.L., Amatrudo, J.M., Kinson, M.S., Todd-Brown, M.A., Lewis, J., Luebke, J.I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2010
• Subjects: Action Potentials - physiology; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Animals; Atrophy; Dendrite; Dendritic spine; Dendritic Spines - pathology; Dendritic Spines - physiology; Frontal; FTDP-17; Humans; In vitro slice; Membrane Potentials - physiology; Mice; Mice, Transgenic; Neurofibrillary Tangles - pathology; Neurofibrillary Tangles - physiology; Organ Culture Techniques; Patch clamp; Patch-Clamp Techniques; Point Mutation; Pyramidal cell; Pyramidal Cells - pathology; Pyramidal Cells - physiology; Pyramidal Cells - ultrastructure; Structure-Activity Relationship; tau Proteins - chemistry; tau Proteins - genetics; Tauopathies - pathology; Tauopathies - physiopathology; Tauopathy; Transgenic model; Pyramidal cell; Transgenic model; FTDP-17; Patch clamp; Dendritic spine; Frontal; Tauopathy; In vitro slice; Alzheimer's disease; Dendrite
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2009.07.029

In the rTg4510 mouse model, expression of the mutant human tau variant P301L leads to development of neurofibrillary tangles (NFTs), neuronal death, and memory impairment, reminiscent of the pathology observed in human tauopathies. In the present study, we examined the effects of mutant tau expression on the electrophysiology and morphology of individual neurons using whole-cell patch-clamp recordings and biocytin filling of pyramidal cells in cortical slices prepared from rTg4510 (TG) and wild-type (WT) littermate mice. Among the TG cells, 42% contained a clear Thioflavin-S positive inclusion in the soma and were categorized as NFT positive (NFT+), while 58% had no discernable inclusion and were categorized as NFT negative (NFT−). The resting membrane potential (
V
r) was significantly depolarized (+
8 mV) in TG cells, and as a consequence, evoked repetitive action potential (AP) firing rates were also significantly increased. Further, single APs were significantly shorter in duration in TG cells and the depolarizing voltage deflection or “sag” evoked by hyperpolarization was significantly greater in amplitude. In addition to these functional electrophysiological changes, TG cells exhibited significant morphological alterations, including loss or significant atrophy of the apical tuft, reduced dendritic complexity and length, and reduced spine density. Importantly, NFT− and NFT+ TG cells were indistinguishable with regard to both morphological and electrophysiological properties. Our observations show that expression of mutated tau results in significant structural and functional changes in neurons, but that these changes occur independent of mature NFT formation.