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

Jiang, T, Handley, EE ORCID: 0000-0002-8809-9126, Brizuela, M, Dawkins, E, Lewis, KE, Clark, RM ORCID: 0000-0001-6156-6671, Dickson, TC ORCID: 0000-0002-9196-1661 and Blizzard, CA ORCID: 0000-0002-8683-2937 2019 , 'Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function' , Disease Models & Mechanisms, vol. 12, no. 5 , pp. 1-11 , doi:

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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-43\(^{A315T}\) In TDP-43\(^{A315T}\) cortical neurons, dendritic spine density was significantly reduced compared to wild-type controls. TDP-43\(^{A315T}\) 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-43\(^{A315T}\) pyramidal neurons. This work reveals a crucial effect of the over-expression mutation TDP-43\(^{A315T}\) 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-43\(^{A315T}\) 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 Type: Article
Authors/Creators:Jiang, T and Handley, EE and Brizuela, M and Dawkins, E and Lewis, KE and Clark, RM and Dickson, TC and Blizzard, CA
Keywords: TDP-43, synapse, dendrite spine, AMPA, excitability
Journal or Publication Title: Disease Models & Mechanisms
Publisher: The Company of Biologists Ltd.
ISSN: 1754-8403
DOI / ID Number:
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Copyright 2019 Published by The Company of Biologists. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

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