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Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function

Citation

Jiang, T and Handley, E and Brizuela, M and Dawkins, E and Lewis, KE and Clark, RM and Dickson, TC and Blizzard, CA, Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function, Disease Models & Mechanisms, 12, (5) pp. 1-11. ISSN 1754-8403 (2019) [Refereed Article]


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Copyright 2019 Published by The Company of Biologists. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1242/dmm.038109

Abstract

Altered cortical excitability and synapse dysfunction are early pathogenic events in amyotrophic lateral sclerosis (ALS) patients and animal models. Recent studies propose an important role for TAR DNA-binding protein 43 (TDP-43), the mislocalization and aggregation of which are key pathological features of ALS. However, the relationship between ALS-linked TDP-43 mutations, excitability and synaptic function is not fully understood. Here, we investigate the role of ALS-linked mutant TDP-43 in synapse formation by examining the morphological, immunocytochemical and excitability profile of transgenic mouse primary cortical pyramidal neurons that over-express human TDP-43A315T In TDP-43A315T cortical neurons, dendritic spine density was significantly reduced compared to wild-type controls. TDP-43A315T over-expression increased the total levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropinionic acid (AMPA) glutamate receptor subunit GluR1, yet the localization of GluR1 to the dendritic spine was reduced. These postsynaptic changes were coupled with a decrease in the amount of the presynaptic marker synaptophysin that colocalized with dendritic spines. Interestingly, action potential generation was reduced in TDP-43A315T pyramidal neurons. This work reveals a crucial effect of the over-expression mutation TDP-43A315T on the formation of synaptic structures and the recruitment of GluR1 to the synaptic membrane. This pathogenic effect may be mediated by cytoplasmic mislocalization of TDP-43A315T Loss of synaptic GluR1, and reduced excitability within pyramidal neurons, implicates hypoexcitability and attenuated synaptic function in the pathogenic decline of neuronal function in TDP-43-associated ALS. Further studies into the mechanisms underlying AMPA receptor-mediated excitability changes within the ALS cortical circuitry may yield novel therapeutic targets for treatment of this devastating disease.

Item Details

Item Type:Refereed Article
Keywords:TDP-43, synapse, dendrite spine, AMPA, excitability
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurology and Neuromuscular Diseases
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
UTAS Author:Jiang, T (Miss Tongcui Jiang)
UTAS Author:Handley, E (Ms Emily Handley)
UTAS Author:Brizuela, M (Mrs Mariana Brizuela)
UTAS Author:Dawkins, E (Dr Edgar Dawkins)
UTAS Author:Lewis, KE (Dr Katherine Lewis)
UTAS Author:Clark, RM (Miss Rosie Clark)
UTAS Author:Dickson, TC (Professor Tracey Dickson)
UTAS Author:Blizzard, CA (Dr Catherine Blizzard)
ID Code:133424
Year Published:2019
Web of Science® Times Cited:1
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-06-27
Last Modified:2019-07-16
Downloads:7 View Download Statistics

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