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Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

Dyer, MS, Reale, LA, Lewis, KE ORCID: 0000-0003-1264-464X, Walker, AK, Dickson, TC ORCID: 0000-0002-9196-1661, Woodhouse, A ORCID: 0000-0002-4246-7624 and Blizzard, CA ORCID: 0000-0002-8683-2937 2020 , 'Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex' , Journal of Neurochemistry, vol. 157, no. 4 , pp. 1300-1315 , doi: 10.1111/jnc.15214.

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Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA-binding protein TAR-DNA-bindingprotein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changesoccurring in people with ALS and mouse models of disease. To investigate the effect of mislocalised TDP-43 on the function of motor cortex neurons we utilisedmouse models that express either human wild-type (TDP-43WT) or nuclear localisation sequence-deficient TDP-43 (TDP-43ΔNLS) on an inducible promoter that enriches expression to forebrain neurons. Pathophysiology was investigated throughimmunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty daysexpression of TDP-43ΔNLS in adult mice did not cause any changes in the number ofCTIP2-positive neurons in the motor cortex. However, at this time-point, the expression of TDP-43ΔNLS drives intrinsic hyperexcitability in layer V excitatory neuronsof the motor cortex. This hyperexcitability occurs concomitantly with a decrease inexcitatory synaptic input to these cells and fluctuations in both directions of ionotropic glutamate receptors. This pathophysiology is not present with TDP-43WT expression, demonstrating that the localisation of TDP-43 to the cytoplasm is crucialfor the altered excitability phenotype. This study has important implications for themechanisms of toxicity of one of the most notorious proteins linked to ALS, TDP-43.We provide the first evidence that TDP-43 mislocalisation causes aberrant synapticfunction and a hyperexcitability phenotype in the motor cortex, linking some of theearliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.

Item Type: Article
Authors/Creators:Dyer, MS and Reale, LA and Lewis, KE and Walker, AK and Dickson, TC and Woodhouse, A and Blizzard, CA
Keywords: ALS, cortex, excitability, glutamate, hyperexcitability, mislocalisation, mouse model, TDP-43
Journal or Publication Title: Journal of Neurochemistry
Publisher: Blackwell Publishing Ltd
ISSN: 0022-3042
DOI / ID Number: 10.1111/jnc.15214
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Copyright 2020 International Society for Neurochemistry

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