Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the mechanisms that underlie cortical hyper-excitability are not completely understood, the molecular and cellular mechanisms that cause enhanced neuronal intrinsic excitability and changes in excitatory and inhibitory synaptic activity are starting to emerge. Here, we review the evidence for an anterograde glutamatergic excitotoxic process, leading to cortical hyper-excitability via intrinsic cellular and synaptic mechanisms and for the role of interneurons in establishing disinhibition in clinical and experimental settings. Understanding the mechanisms that lead to these complex pathological processes will likely produce key insights towards developing novel therapeutic strategies to rescue upper MNs, thus alleviating the impact of this fatal disease.
Highlights
First described by Jean-Martin Charcot in 1869, amyotrophic lateral sclerosis (ALS), one of the most common neuromotor diseases, is characterized by an inexorable loss of upper and lower motor neurons (MNs)
Lower MNs are the final output pathway that integrate motor output and regulate muscle activity, the presence of corticospinal monosynaptic or polysynaptic axonal projections that originate in the primary motor cortex, dorsal prefrontal cortex and somatosensory cortex [3,4] and relay cortical output to the lower motor neurons (LMNs) allow fine regulation of neuromotor execution in humans [5]
A clear family history is present in only 10% of all ALS cases and has been increasingly associated with a genetic cause, while the remaining 90% have no family history and are classified as sporadic ALS, a genetic cause can be identified in about 10% of these patients [2,10,11]
Summary
First described by Jean-Martin Charcot in 1869, amyotrophic lateral sclerosis (ALS), one of the most common neuromotor diseases, is characterized by an inexorable loss of upper and lower motor neurons (MNs). The upper motor neurons of the primary motor cortex are large pyramidal neurons in layer V (LVPNs), whose axonal projections form the corticospinal tracts, which descend to directly or indirectly excite the lower motor neurons (LMNs) of brainstem and the spinal cord [1,2]. Lower MNs are the final output pathway that integrate motor output and regulate muscle activity, the presence of corticospinal monosynaptic or polysynaptic axonal projections that originate in the primary motor cortex, dorsal prefrontal cortex and somatosensory cortex [3,4] and relay cortical output to the LMNs allow fine regulation of neuromotor execution in humans [5]. MNs is glutamate-induced excitotoxicity which results from either excessive presynaptic glutamate release or defective glutamate reuptake This depolarizes the post-synaptic neuron and increases calcium influx, leading to hyper-excitability [12,13]. This review concentrates on the neurophysiology of hyper-excitability in upper MNs and the probable mechanisms involved
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