Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model

Zainuddin Quadri, Nicholas Johnson, Frank Zamudio, Abraian Miller, Melinda Peters, Shayna Smeltzer, Jerry B. Hunt, Steven B. Housley, Breanna Brown, Susan Kramer, Christopher M. Norris, Kevin Nash, Edwin Weeber, Daniel C. Lee, Maj Linda B. Selenica

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Aims: The current study utilizes the adeno-associated viral gene transfer system in the CAMKIIα-tTA mouse model to overexpress human wild type TDP-43 (wtTDP-43) and α-synuclein (α-Syn) proteins. The co-existence of these proteins is evident in the pathology of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Parkinson disease (PD), and dementia with Lewy bodies (DLB). Methods: The novel bicistronic recombinant adeno-associated virus (rAAV) serotype 9 drives wtTDP-43 and α-Syn expression in the hippocampus via “TetO” CMV promoter. Behavior, electrophysiology, and biochemical and histological assays were used to validate neuropathology. Results: We report that overexpression of wtTDP-43 but not α-Syn contributes to hippocampal CA2–specific pyramidal neuronal loss and overall hippocampal atrophy. Further, we report a reduction of hippocampal long-term potentiation and decline in learning and memory performance of wtTDP-43 expressing mice. Elevated wtTDP-43 levels induced selective degeneration of Purkinje cell protein 4 (PCP-4) positive neurons while both wtTDP-43 and α-Syn expression reduced subsets of the glutamate receptor expression in the hippocampus. Conclusions: Overall, our findings suggest the significant vulnerability of hippocampal neurons toward elevated wtTDP-43 levels possibly via PCP-4 and GluR-dependent calcium signaling pathways. Further, we report that wtTDP-43 expression induced selective CA2 subfield degeneration, contributing to the deterioration of the hippocampal-dependent cognitive phenotype.

Original languageEnglish
Article number103418
JournalMolecular and Cellular Neuroscience
Volume102
DOIs
StatePublished - Jan 2020

Bibliographical note

Funding Information:
This work was supported by the start-up funds and New Investigator Seed Grant provided by the College of Pharmacy, University of South Florida, US. Animal procedures were consistent with the recommendations of the National Research Council's “Guide for the Care and Use of Laboratory Animals,” and were approved by the University of South Florida animal care and use committee (IACUC). Z.Q. was involved in the electrophysiology recordings, Western blotting, analysis and interpretation of the LTP results, assisted in figure and manuscript preparation. N.J. performed immunohistochemistry, analyzed data and was involved in the preparation of the figures and manuscript. F.K. performed fluorescence immunohistochemistry, Western blotting, stereology, and analyzed the HPC/CA2 volume. SHV performed fluorescence immunohistochemistry and confocal imaging. M.P. performed the electrophysiology recordings, analyzed data, and prepared figures. S.L.S. performed mouse behavior testing and analyzed results. S.B.H and J.H performed mouse surgeries. B.B performed immunohistochemical analyses and prepared figures. J.L and A.M. performed Western blotting and analyzed the data. K.N. prepared the viruses. C.M.N and S.K. performed Western blotting and provided GluR antibodies. E. W. assisted with the design of the electrophysiology recordings and interpretation of the findings. D.C.L. assisted with surgeries and revisions of the manuscript. M.L.B.S. conceived the experimental plan, provided funding, assisted with data interpretation, figure and manuscript preparation, and revision of the manuscript. All authors declare no conflict of interest.

Funding Information:
This work was supported by the start-up funds and New Investigator Seed Grant provided by the College of Pharmacy , University of South Florida , US.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • ALS
  • CA2
  • FTLD
  • Glutamate receptor
  • Hippocampus
  • Learning
  • PCP-4
  • Synaptic plasticity
  • TDP-43
  • α-Synuclein

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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