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

6 Scopus citations


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
StatePublished - Jan 2020

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.


  • 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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