Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Abstract

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. 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. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. 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. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. 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. 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. 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.

ILB®, a Low Molecular Weight Dextran Sulphate, Restores Glutamate Homeostasis, Amino Acid Metabolism and Neurocognitive Functions in a Rat Model of Severe Traumatic Brain Injury

“…The common feature among all TBI is that part of the energy associated with the traumatic event (primary injury) is absorbed by the brain tissue, invariably triggering a plethora of biochemical, metabolic, and molecular alterations (secondary injury), profoundly affecting various biological processes and functions of neuronal cells [ 2 , 3 ]. Among them, glutamate (Glu) excitotoxicity [ 4 , 5 , 6 , 7 ] and alterations of the brain levels of numerous free amino acids (FAA) involved in relevant biochemical activities [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] have been reported to occur following TBI. For these reasons, TBI patients are still in search of valid pharmacological treatments that can ameliorate their outcome.…”

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

“…These ligand-gated ion channels have inspired a large number of studies because of their various structural subtypes and unique physiological functions [ 126 ]. NMDA receptor is an important target in clinical research of ischemic stroke, which is mainly located in dendritic spines, perisynaptic areas, and extra-synaptic areas [ 12 ]. It is generally believed that compared with AMPA and KA receptors, NMDA receptors are the most effective agonists for inducing neurotoxicity due to their higher voltage-dependent flux and permeability to calcium ions, and do not show concentration-dependent desensitization of glutamate [ 125 ].…”

“…After glutamate releasing from the presynapse, the activation of AMPAR removes magnesium ions blocking NMDAR channels, then NMDAR acts as an effective “coincidence detector” to transport Na 2+ and Ca 2+ into cells [ 127 , 128 ]. In addition, the coupling of various death-related signals related to the cytoplasmic tail of the NMDAR initiates a series of postsynaptic death events, which may also be the reason why synaptic NMDAR-mediated calcium currents can cause greater neurotoxicity than other calcium sources [ 12 , 38 ].…”

“…Following cerebral ischemia, largely increased glutamate emanates from nerve terminals and astrocytes due to anoxic depolarizations within minutes, accompanied by impaired reuptake, ultimately leading to excessive accumulation in the ischemic regions of the brain [ 10 ]. In classical excitotoxicity, the subsequent activation of ionic glutamate receptors represented by NMDAR causes the intracellular Ca 2+ overload and initiation of downstream cell death events, such as nNOS/NOX 2 activation, ROS/RNS generation, and mitochondrial dysfunctions [ 11 , 12 , 13 , 14 ]. Overall, neuronal cells in the ischemic brain would inevitably be exposed to cumulative excitotoxicity.…”

More Attention on Segments Remote from the Primary Spinal Cord Lesion Site

“…There is now significant evidence that degeneration of presynaptic terminals precedes neuronal death in chronic neurodegenerative diseases of the CNS [25,26]. However, the contribution of axotomy to the neuronal loss in SCI remains controversial.…”