TDP-43 PATHOLOGY DRIVES MOTONEURONE HYPEREXCITABILITY IN A CELL-AUTONOMOUS MANNER

The most common molecular hallmark of Amyotrophic lateral sclerosis (ALS) is cytosolic aggregation of transactive response DNA-binding protein 43 kDa (TDP-43), which is present in ≥97% of patients with ALS and ~50% of patients with Frontotemporal dementia (FTD). Hyperexcitability in the motor system is a consistent feature of ALS. It has previously been shown that pathological TDP-43 is sufficient to drive spinal motoneurone hyperexcitability when expressed ubiquitously in all neurons using the TDP43-ΔNLS mouse model of ALS by using the NEFH promoter.
In this study, we aimed to investigate if this hyperexcitability is driven directly by cell-autonomous effects of TDP-43, or if it represents a homeostatic response to changes in the motor network projecting to the motoneurones. To test this, we used the same TDP-43-ΔNLS mouse model but with a CamKIIa-tTa/tetO promoter, which restricts the expression of the pathological TDP-43 to predominantly cortical neurons, including corticospinal tract motoneurones. We then recorded the electrophysiological properties of spinal motoneurones using in-vivo intracellular recording at four weeks post induction (the same timepoint that hyperexcitability is seen in the TDP43-ΔNLS-NEFH mouse).
Our recordings revealed that the excitability of the spinal motoneurones was not affected by the cortically expressed TDP-43 pathology, with no significant changes in rheobase, voltage threshold or I-f gain. Therefore, we conclude that the excitability changes observed in the TDP43-ΔNLS-NEFH are driven in a cell-autonomous manner by the TDP-43 pathology in the cell itself. This suggests that strategies to reduce hyperexcitability in this disease should focus on TDP-43 pathology.