Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA-binding protein TAR-DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changes occurring 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 utilised mouse models that express either human wild-type (TDP-43^WT) or nuclear localisation sequence-deficient TDP-43 (TDP-43^ΔNLS) on an inducible promoter that enriches expression to forebrain neurons. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression of TDP-43^ΔNLS in adult mice did not cause any changes in the number of CTIP2-positive neurons in the motor cortex. However, at this time-point, the expression of TDP-43^ΔNLS drives intrinsic hyperexcitability in layer V excitatory neurons of the motor cortex. This hyperexcitability occurs concomitantly with a decrease in excitatory synaptic input to these cells and fluctuations in both directions of ionotropic glutamate receptors. This pathophysiology is not present with TDP-43^WT expression, demonstrating that the localisation of TDP-43 to the cytoplasm is crucial for the altered excitability phenotype. This study has important implications for the mechanisms 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 synaptic function and a hyperexcitability phenotype in the motor cortex, linking some of the earliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.

Item Type:	Refereed Article
Keywords:	ALS, cortex, excitability, glutamate, hyperexcitability, mislocalisation, mouse model, TDP-43
Research Division:	Biomedical and Clinical Sciences
Research Group:	Neurosciences
Research Field:	Neurology and neuromuscular diseases
Objective Division:	Expanding Knowledge
Objective Group:	Expanding knowledge
Objective Field:	Expanding knowledge in the biomedical and clinical sciences
UTAS Author:	Dyer, MS (Mr Marcus Dyer)
UTAS Author:	Reale, LA (Ms Laura Reale)
UTAS Author:	Lewis, KE (Dr Katherine Lewis)
UTAS Author:	Walker, AK (Mr Adam Walker)
UTAS Author:	Dickson, TC (Professor Tracey Dickson)
UTAS Author:	Woodhouse, A (Dr Adele Woodhouse)
UTAS Author:	Blizzard, CA (Dr Catherine Blizzard)
ID Code:	144031
Year Published:	2020
Web of Science® Times Cited:	15
Deposited By:	Wicking Dementia Research and Education Centre
Deposited On:	2021-04-15
Last Modified:	2022-08-23
Downloads:	0