Neuronal TDP-43 depletion affects activity-dependent plasticity

Neurobiol Dis. 2019 Oct;130:104499. doi: 10.1016/j.nbd.2019.104499. Epub 2019 Jun 6.

Abstract

TAR DNA-binding protein 43 (TDP-43) is a hallmark of some neurodegenerative disorders, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. TDP-43-related pathology is characterized by its abnormally phosphorylated and ubiquitinated aggregates. It is involved in many aspects of RNA processing, including mRNA splicing, transport, and translation. However, its exact physiological function and role in mechanisms that lead to neuronal degeneration remain elusive. Transgenic rats that were characterized by TDP-43 depletion in neurons exhibited enhancement of the acquisition of fear memory. At the cellular level, TDP-43-depleted neurons exhibited a decrease in the short-term plasticity of intrinsic neuronal excitability. The induction of long-term potentiation in the CA3-CA1 areas of the hippocampus resulted in more stable synaptic enhancement. At the molecular level, the protein levels of an unedited (R) FLOP variant of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluR1 and GluR2/3 subunits decreased in the hippocampus. Alterations of FLOP/FLIP subunit composition affected AMPAR kinetics, reflected by cyclothiazide-dependent slowing of the decay time of AMPAR-mediated miniature excitatory postsynaptic currents. These findings suggest that TDP-43 may regulate activity-dependent neuronal plasticity, possibly by regulating the splicing of genes that are responsible for fast synaptic transmission and membrane potential.

Keywords: AMPA receptors; FLOP/FLIP splice variants; PTZ model; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dendritic Spines / metabolism
  • Hippocampus / metabolism*
  • Memory / physiology*
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism*
  • Rats
  • Rats, Transgenic
  • Receptors, AMPA / metabolism
  • Synaptic Transmission / physiology

Substances

  • DNA-Binding Proteins
  • Receptors, AMPA
  • Tardbp protein, rat