Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the degeneration of cortical and spinal motor neurons. With no effective treatment available to date, patients face progressive paralysis and eventually succumb to the disease due to respiratory failure within only a few years. Recent research has revealed the multifaceted nature of the mechanisms and cell types involved in motor neuron degeneration, thereby opening up new therapeutic avenues. Intriguingly, two key features present in both ALS patients and rodent models of the disease are cortical hyperexcitability and hyperconnectivity, the mechanisms of which are still not fully understood. We here recapitulate current findings arguing for cell autonomous and non-cell autonomous mechanisms causing cortical excitation and inhibition imbalance, which is involved in the degeneration of motor neurons in ALS. Moreover, we will highlight recent evidence that strongly indicates a cardinal role for the motor cortex as a main driver and source of the disease, thus arguing for a corticofugal trajectory of the pathology.
Highlights
Amyotrophic lateral sclerosis (ALS) is a lethal disease that is primarily characterized by the loss of upper motor neurons (UMN) in the cortex and lower motor neurons (LMN) in the spinal cord [1,2]
While some believe the initial pathology occurs at the level of lower motor neurons (LMN) in the spinal cord or even the neuro-muscular junction [29,30], with the cortex and UMN being affected in a retrograde process, others argue that the disease originates in the cortex and propagates in a corticofugal manner to subsequently affect LMN in the spinal cord [30,31]
What are the mechanisms leading to early cortical hyperexcitability? Alterations in the net motor cortex excitability can be driven by intrinsic mechanisms, affecting the main motor cortex output population—the UMN—and/or by extrinsic mechanisms, inflicted by cells other than UMN, such as altered glutamatergic or GABAergic neurons or glia cells
Summary
Amyotrophic lateral sclerosis (ALS) is a lethal disease that is primarily characterized by the loss of upper motor neurons (UMN) in the cortex and lower motor neurons (LMN) in the spinal cord [1,2]. An ever-growing list of genes and gene variants is linked to the development of ALS [4], but only a mere 5–10% of all cases are familial (fALS) due to inherited genetic mutations, while the large majority of cases (90–95%) are sporadic (sALS) [5,6,7]. Both forms of the disease progress rapidly. We will summarize recent evidence for cortical hyperexcitability in both humans and rodent models of ALS and recapitulate the currently known underlying cellular and circuit mechanisms
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