Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability.

Chemogenetic manipulation of CX3CR1 cells transiently induces hypolocomotion independent of microglia.

Chemogenetic approaches using Designer Receptors Exclusively Activated by Designer Drugs (DREADD, a family of engineered GPCRs) were recently employed in microglia. Here, we used Cx3cr1:R26 mice to express Gi-DREADD (hM4Di) on CX3CR1 cells, comprising microglia and some peripheral immune cells, and found that activation of hM4Di on long-lived CX3CR1 cells induced hypolocomotion. Unexpectedly, Gi-DREADD-induced hypolocomotion was preserved when microglia were depleted.

Spinal microglia contribute to sustained inflammatory pain via amplifying neuronal activity.

Microglia are highly dynamic immune cells of the central nervous system (CNS). Microglial processes interact with neuronal elements constantly on the order of minutes. The functional significance of this acute microglia-neuron interaction and its potential role in the context of pain is still largely unknown.

Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain.

Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain.