Fig. 3

The non-cell-autonomous mechanisms of UMN hyperexcitability in ALS: astrocyte dysfunction. Representation of astrocyte-neuron interaction in ALS. A Defective astrocytes lead to an accumulation of glutamate in the synaptic cleft, resulting from both a loss of glutamate uptake through astrocyte excitatory amino acid transporters (EAAT1/GLAST and EAAT2/GLT1) and an excessive release of glutamate caused by disruption of Ca²⁺ homeostasis in astrocytes. These defects contribute to hyperexcitability of upper motor neurons (UMNs). Impaired Ca²⁺ homeostasis in astrocytes may be due to increased permeability of Ca²⁺ receptors/channels (transient receptor potential ankyrin 1 (TRPA1), AMPA, NMDA and P2X receptors), increased Ca²⁺ release from internal stores (endoplasmic reticulum, ER) via activation of G protein-coupled receptors (GPCRs) and reversed operation of the sodium-calcium exchanger NCX. B Defective astrocytes cause an ionic imbalance in the synaptic cleft due to dysfunction of astrocytic Kir4.1 channels and sodium–potassium-ATPase (NKA). This results in an accumulation of K⁺ in the synaptic cleft, which leads to abnormal firing of neurons. Activity-dependent Na⁺ transients switch NCX to a “reverse mode” by mediating Ca²⁺ import and Na⁺ export. C Defective astrocytes become less efficiency in providing metabolic support for neurons. Disrupting the expression of the astrocytic lactate transporters, monocarboxylate transporter 4 (MCT4) or MCT1, results in decreased lactate support for neurons. D Defective astrocytes release lower levels of neurotrophic factors [such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF)] and produce abnormal levels of cytokines and other toxic substances [such as transforming growth factor beta 1 (TGF-β1), interferon alpha (IFN- α), interferon gamma (IFN- γ), interleukin 6 (IL- 6), reactive oxygen species (ROS), and nitric oxide (NO)]. Microglia produce tumor necrosis factor alpha (TNF-α), interleukin 1 alpha (IL-1α), and complement component 1q (C1q) to trigger the activation of neurotoxic reactive astrocytes