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Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy

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Abstract

Whole-cell patch-clamp recordings and high-resolution morphometry were used to assess functional and structural properties of layer 3 pyramidal neurons in early (<4 months) and advanced (>8 months) stages of tauopathy in frontal cortical slices prepared from rTg4510 tau mutant (P301L) mice. In early tauopathy, dendritic architecture is preserved. In advanced tauopathy, neurons can be categorized as either “atrophic” (58 %)—exhibiting marked atrophy of the apical tuft, or “intact” (42 %)—with normal apical tufts and, in some instances, proliferative sprouting of oblique branches of the apical trunk. Approximately equal numbers of atrophic and intact neurons contain neurofibrillary tangles (NFTs) or are tangle-free, lending further support to the idea that NFTs per se are not toxic. Spine density is decreased due to a specific reduction in mushroom spines, but filopodia are increased in both atrophic and intact neurons. By contrast to these morphological changes, which are robust only in the advanced stage, significant electrophysiological changes are present in the early stage and persist in the advanced stage in both atrophic and intact neurons. The most marked of these changes are: a depolarized resting membrane potential, an increased depolarizing sag potential and increased action potential firing rates—all indicative of hyperexcitability. Spontaneous excitatory postsynaptic currents are not reduced in frequency or amplitude in either stage. The difference in the time course of functionally important electrophysiological changes versus regressive morphological changes implies differences in pathogenic mechanisms underlying functional and structural changes to neurons during progressive tauopathy.

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Acknowledgments

The authors declare no competing financial interests. This work was supported by NIH/NIA grants R01-AG025062. The authors are grateful to Dr. Jada Lewis for generously providing us with rTg4510 mice, Joseph Amatrudo for assistance with data collection, Dr. Christina Weaver for assistance with statistical analyses, Dr. Maria Medalla for careful reading of the manuscript, and Dr. Tara Spires-Jones for helpful discussions throughout the course of this project.

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  1. L-1004, Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord St., Boston, MA, 02118, USA

    Johanna L. Crimins, Anne B. Rocher & Jennifer I. Luebke

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  1. Johanna L. Crimins
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Correspondence to Jennifer I. Luebke.

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Crimins, J.L., Rocher, A.B. & Luebke, J.I. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol 124, 777–795 (2012). https://doi.org/10.1007/s00401-012-1038-9

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