![]() ![]() NMDAR and AMPAR are localized predominantly to dendritic spines, but also exist in perisynaptic and extrasynaptic regions. Glutamate binds to calcium-permeable ionotropic receptors called N-methyl- D-aspartate (NMDA) receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) due to their ability to be activated by NMDA or AMPA, respectively. Moreover, sublethal glutamatergic injury contributes to dendritic degeneration accompanied by mitochondrial calcium toxicity. However, excessive glutamatergic input elicits excitotoxicity, contributing to neuronal cell death following acute hypoxic-ischemic insults or traumatic brain injury. Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington’s disease. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl- D-aspartate receptor antagonists. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. ![]() ![]()
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