Fig. 2

The cell-autonomous mechanisms of UMN hyperexcitability in ALS. Cell-autonomous mechanisms refer to the change in intrinsic properties of upper motor neurons (UMNs) that contribute to the hyperexcitability. A Representation of an excitatory synapse in ALS. Glutamatergic signaling mediated UMN hyperexcitability can be caused by various mechanisms: 1) increased expression levels and/or modifications of the glutamate receptors [such as N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and kainate receptor (KAR)]; 2) increased presynaptic glutamate release and, 3) decreased glutamate removal by glial cells. Ion channel dysfunctions also contribute to hyperexcitability, such as increased inward Na⁺ current and decreased outward K⁺ current, resulting in an increased repetitive firing of UMNs. B Representation of an inhibitory synapse in ALS. Loss or dysfunction of inhibitory neurons and alteration of inhibitory neurotransmitter receptors (such as GABAR) impaired inhibitory circuits, leading to UMN hyperexcitability. C Representation of impaired Ca²⁺ homeostasis in synapse in ALS. Increased cytosolic Ca ²⁺ triggers presynaptic glutamate release and regulates postsynaptic glutamate receptors efficiency, contributing to UMN hyperexcitability. The mechanisms underlying abnormal Ca²⁺ homeostasis include abnormal expression of Ca²⁺ permeable channels and pumps, dysfunction of endoplasmic reticulum (ER) and mitochondrial due to oxidative stress, and an impaired Ca²⁺ buffering system. D Representation of neuromodulator regulation in synapses in ALS. The neuromodulator regulation is crucial for fine-tuning and coordinating complex motor cortical circuits. Changes in neuromodulator levels may also be involved in the development of cortical hyperexcitability in ALS