Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex
Dyer, MS and Reale, LA and Lewis, KE and Walker, AK and Dickson, TC and Woodhouse, A and Blizzard, CA, Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex, Journal of Neurochemistry ISSN 0022-3042 (2020) [Refereed Article]
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-43WT) or nuclear localisation sequence-deficient TDP-43 (TDP-43ΔNLS) 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-43ΔNLS 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-43ΔNLS 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-43WT 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.