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

Mol Cell Neurosci. 2020 Jan:102:103418. doi: 10.1016/j.mcn.2019.103418. Epub 2019 Nov 6.


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.

Keywords: ALS; CA2; FTLD; Glutamate receptor; Hippocampus; Learning; PCP-4; Synaptic plasticity; TDP-43; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA2 Region, Hippocampal / metabolism*
  • CA2 Region, Hippocampal / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Long-Term Potentiation*
  • Maze Learning
  • Memory*
  • Mice
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism
  • alpha-Synuclein / metabolism


  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Neuropeptides
  • Pcp2 protein, mouse
  • Receptors, Glutamate
  • TARDBP protein, human
  • alpha-Synuclein
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2