Mechanisms of neurophysiological impairments in the cortex and lower motor neurons in C9ORF72RE amyotrophic lateral sclerosis

In humans, upper motor neurons (blue) descend from the motor cortex and project onto the brainstem and spinal cord via the corticospinal tract. These corticospinal neurons form a monosynaptic pathway (in primates and humans) that innervates lower motor neurons (orange), which in turn transmit motor signals to effector muscles. Together this forms the motor circuitry within humans. Neurophysiological impairments leading to amyotrophic lateral sclerosis can arise in the corticospinal tract at various loci. In amyotrophic lateral sclerosis, cortical dysfunction ranges from hyperexcitability (increased excitability) as a result of increased excitatory signaling or reduced inhibition, disruption of synaptic vesicle dynamics, and impaired synaptic plasticity that also extends to cortico-hippocampal connections. Within the corticospinal tract, upper motor neurons are vulnerable to synaptic loss and dendrite pathology including loss of dendritic spines that may arise from increased hyperexcitability. In a feedforward mechanism of dysfunction, degeneration of lower motor neurons is mediated, at least in part, via glutamate-mediated excitotoxicity whereby, cortical dysfunction precedes that of lower motor neurons, potentially causing further neurophysiological impairments and injury in lower motor neurons. (Reproduced with author permission from: Pasniceanu IS, Atwal MS, Souza CD, et al. Emerging mechanisms underpinning neurophysiological impairments in C9ORF72 repeat expansion-mediated amyotrophic lateral sclerosis/frontotemporal dementia. Front Cell Neurosci 2021;15: 784833.)