Amyotrophic lateral sclerosis associated mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex.

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 mislocalized TDP-43 on the function of motor cortex neurons we utilised mouse models that express either human wild-type (TDP-43WT) or nuclear localization sequence-deficient TDP-43 (TDP-43{Delta}NLS) on an inducible promoter that is restricted to the forebrain. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression TDP-43{Delta}NLS in adult mice (60 days of age) does not cause any changes in the number of NeuN positive nor CTIP2 positive neurons in the motor cortex. However at this time-point the expression of TDP-43{Delta}NLS 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. This pathophysiology is not present when TDP-43WT expression is driven, 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 mislocalization 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.