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Neurobiol Dis. 2019 Jun 6;130:104499. doi: 10.1016/j.nbd.2019.104499. [Epub ahead of print]

Neuronal TDP-43 depletion affects activity-dependent plasticity.

Author information

1
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
2
Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Warsaw, Poland.
3
BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
4
BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Electronic address: l.kaczmarek@nencki.gov.pl.
5
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Electronic address: w.konopka@nencki.gov.pl.

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

PMID:
31176717
DOI:
10.1016/j.nbd.2019.104499

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