|MT > 17. The Origin of Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis|
It has been well established that amyotrophic lateral sclerosis (ALS) originates from hyperexcitability in the cerebral cortex (Eisen et al., 1993; Vucic et al., 2008; Menon et al., 2015). Compelling evidence has also revealed that in ALS hyperexcitability of corticospinal motor neurons precedes excitotoxicity in the brainstem and spinal cord (see Article 1). The corticospinal motor neurons project from motor cortex layer V to the spinal cord motor neurons. However, their hyperexcitability may not be the origin of ALS. A report suggests that the abnormality of motor cortex occurs first in layer III pyramidal neurons, rather than the layer V corticospinal motor neurons which include the giant Betz cells (Sasaki and Maruyama, 1994). This notion is supported by a recent finding that ALS could originate from hyperactive somatostatin-positive interneurons (SOM cells) (Zhang et al., 2016).
The Role of SOM Cells in ALS
Both ALS and Parkinson's disease are movement disorders. As discussed in Chapter 14, beta oscillations (13 - 30 Hz) play a crucial role in body movement. Altered cortical beta oscillations have been shown to reflect motor system degeneration in ALS (Proudfoot et al., 2017; Proudfoot et al., 2018). SOM cells fire mainly in the beta band with low threshold, thus also called low-threshold-spiking (LTS) interneurons (Mancilla et al., 2007). Remarkably, in a mouse model of ALS using mutant TDP-43, hyperactive SOM cells have been demonstrated to induce excitotoxicity of layer V (L5) pyramidal neurons by inhibiting PV interneurons (Zhang et al., 2016). This result, together with the finding of Sasaki and Maruyama (1994), suggest that ALS could originate from hyperactive SOM cells and/or pyramidal neurons in the layer III (L3), leading to excitotoxicity of L5 pyramidal neurons (Betz cells). Based on these findings and the BDNF Cascade Hypothesis of Alzheimer's disease, the pathogenic cascade for ALS is proposed in Figure 1.
The loss of TDP-43 function due to mutation, phosphorylation or cleavage may reduce miR-132 level (see Article 1). Thus, this pathogenic cascade is consistent with the observations that miR-132 is down-regulated in TDP-43 (encoded by the TARDBP gene), but not SOD1 mutant patients (Freischmidt et al., 2013).
The Role of mTOR in ALS
The mechanistic target of rapamycin (mTOR) has been shown to stimulate Tau production (see Article 2) and in turn increase neuronal excitability (Article 3). Several lines of evidence suggest that hyperactive mTOR may contribute to the development of ALS:
Hyperactive corticospinal motor neurons in L5 may lead to hyperexcitability of lower motor neurons in the brainstem and spinal cord, resulting in TDP-43 pathology in these motor neurons. Further details are discussed in Article 1.
Author: Frank Lee