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Published on: August 15, 2012
Dysfunction of Glutamate Receptors in Microglia May Cause Neurodegeneration
1Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. noda@phar.kyushu-u.ac.jp.
Abstract:
Dysregulation of glutamate signalling is important in Alzheimer's disease and other pathologies. There has been a focus on changes in neuronal glutamate signalling, but microglia also express glutamate receptors (GluRs), which are known to modulate their responses to neuropathology. Microglia express both metabotropic and ionotropic GluRs. Among ionotropic GluRs, microglial AMPA (α-amino-hydroxy-5-methyl-isoxazole-4-propionate)-type of GluRs (AMPA-Rs) are Ca2+ impermeable due to the expression of subunit GluA2. Upon activation of microglia, expression level of surface GluA2 subunits significantly increase, while expression of GluA1, A3 and A4 subunits on membrane surface significantly decrease. Owing to the GluA2 subunits-dominant composition, AMPA-Rs in activated microglia show little response to Glu. On the other hand, microglia lacking GluA2 show higher Ca(2+)-permeability, consequently inducing a significant increase in the release of the pro-inflammatory cytokine, such as TNF-α. It is suggested that membrane translocation of GluA2-containing AMPA-Rs in activated microglia has functional importance. Thus, dysfunction or decreased expression of GluA2 reported in patients with neurodegenerative diseases such as Alzheimer's and Creutzfeldt-Jakob disease may accelerate Glu neurotoxicity via excess release of proinflammatory cytokines from microglia, causing more neuronal death.
Insights
Microglia
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Glutamate signaling dysregulation is implicated in Alzheimer's disease.
- Microglia, immune cells in the brain, express glutamate receptors (GluRs) that modulate neuropathology.
- Neuronal GluRs have been studied, but microglial GluRs' role is less understood.
Purpose of the Study:
- To investigate the role of microglial AMPA-type glutamate receptors (AMPA-Rs), specifically the GluA2 subunit, in neuropathology.
- To understand how microglial AMPA-R composition changes upon activation and its impact on inflammatory responses.
Main Methods:
- Analysis of microglial glutamate receptor subunit expression (GluA1-A4, GluA2) on the cell surface.
- Assessment of calcium (Ca2+) permeability through microglial AMPA-Rs.
- Measurement of pro-inflammatory cytokine release (e.g., TNF-α) from activated microglia.
Main Results:
- Activated microglia show increased surface expression of GluA2-containing AMPA-Rs, making them Ca2+ impermeable.
- Microglia lacking GluA2 exhibit increased Ca2+ permeability and elevated release of pro-inflammatory cytokines like TNF-α.
- Dysfunction or reduced GluA2 expression in neurodegenerative diseases may enhance microglial inflammatory responses.
Conclusions:
- The composition of microglial AMPA-Rs, particularly the presence of GluA2, is critical for regulating microglial inflammatory responses.
- Altered GluA2 expression in neurodegenerative diseases like Alzheimer's may exacerbate neurotoxicity through excessive pro-inflammatory cytokine release.
- Targeting microglial GluA2 could be a therapeutic strategy for neurodegenerative conditions.
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