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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) Article dmm038109. ISSN 1754-8403 (2019) [Refereed Article]
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Copyright Statement
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/
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: | Biomedical and Clinical Sciences |
| Research Group: | Neurosciences |
| Research Field: | Neurology and neuromuscular diseases |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Clinical health not elsewhere classified |
| 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 (Dr 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: | 13 |
| Deposited By: | Menzies Institute for Medical Research |
| Deposited On: | 2019-06-27 |
| Last Modified: | 2020-08-12 |
| Downloads: | 19 View Download Statistics |
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