The reason for the selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is primarily unknown A possible factor is the expression by motor neurons of Ca(2+)-permeable AMPA/kainate channels, which may permit rapid Ca(2+) influx in response to synaptic receptor activation However, other subpopulations of central neurons, most notably forebrain GABAergic interneurons, consistently express large numbers of these channels but do not degenerate in ALS Indeed, when subjected to identical excitotoxic exposures, motor neurons were more susceptible than GABAergic neurons to AMPA/kainate receptor-mediated neurotoxicity Microfluorimetric studies were performed to examine the basis for the difference in vulnerability First, AMPA or kainate exposures appeared to trigger substantial mitochondrial Ca(2+) loading in motor neurons, as indicated by a sharp increase in intracellular Ca(2+) after addition of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl hydrazone (FCCP) after the agonist exposure The same exposures caused little mitochondrial Ca(2+) accumulation in GABAergic cortical neurons Subsequent experiments examined other measures of mitochondrial function to compare sequelae of AMPA/kainate receptor activation between these populations Brief exposure to either AMPA or kainate caused mitochondrial depolarization, assessed using tetramethylrhodamine ethylester, and reactive oxygen species (ROS) generation, assessed using hydroethidine, in motor neurons However, these effects were only seen in the GABAergic neurons after exposure to the nondesensitizing AMPA receptor agonist kainate Finally, addition of either antioxidants or toxins (FCCP or CN(-)) that block mitochondrial Ca(2+) uptake attenuated AMPA/kainate receptor-mediated motor neuron injury, suggesting that the mitochondrial Ca(2+) uptake and consequent ROS generation are central to the injury process

https://www.jneurosci.org/content/jneuro/20/1/240.full.pdf

AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro.

Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.

/pdf/molecular-factors-underlying-selective-vulnerability-of-u40t75ubyg.pdf

Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis.

Ca2+-permeable AMPA receptors and selective vulnerability of motor neurons

AMPA receptor-mediated excitotoxicity is proposed to play a major pathogenic role in the selective motoneuron death of amyotrophic lateral sclerosis. Motoneurons have been shown in various models to be more susceptible to AMPA receptor-mediated injury than other spinal neurons. It has been hypothesized that this selective vulnerability of motoneurons is caused by the expression of highly Ca(2+)-permeable AMPA receptors and a complete or relative lack of the AMPA receptor subunit Glu receptor 2 (GluR2). The aim of this study was to quantify the relative Ca(2+) permeability of AMPA receptors and the fractional expression of GluR2 in motoneurons by combining whole-cell patch-clamp electrophysiology and single-cell RT-PCR and to compare these properties with those of dorsal horn neurons. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. As in previous studies, motoneurons were significantly more vulnerable to AMPA and kainate than dorsal horn neurons. However, all motoneurons expressed GluR2 mRNA ( approximately 40% of total AMPA receptor subunit mRNA), and their AMPA receptors had intermediate whole-cell relative Ca(2+) permeability (P(Ca(2+))/P(Cs(+)) approximately 0. 4). AMPA receptor P(Ca(2+))/P(Cs(+)) and the relative abundance of GluR2 varied more widely in dorsal horn neurons than in motoneurons, but the mean values did not differ significantly between the two cell populations. GluR2 was virtually completely edited at the Q/R site both in motoneurons and dorsal horn neurons. These results indicate that the selective vulnerability of motoneurons to AMPA receptor agonists is not determined solely by whole-cell relative Ca(2+) permeability of AMPA receptors.

https://www.jneurosci.org/content/jneuro/20/1/123.full.pdf

AMPA Receptor Calcium Permeability, GluR2 Expression, and Selective Motoneuron Vulnerability

Section I: Molecula r Structure of Glutamate Receptors.- 1 Structure of Ionotropic Glutamate Receptors.- 2 Phosphorylation of Glutamate Receptors.- 3 The Synaptic Protein Network Associated with Ionotropic Glutamate Receptors.- 4 Cellular and Subcellular Distribution of Glutamate Receptors.- Section II: Functional Properties of Glutamate Receptors.- 5 Activation of Single AMPA- and NMDA-Type Glutamate-Receptor Channels.- 6 The Ion-Conducting Pore of Glutamate Receptor Channels.- 7 Block of AMPA and Kainate Receptors by Polyamines and Arthropod Toxins.- 8 Kainate Receptors.- 9 Molecular Determinants Controlling Functional Properties of AMPARs and NMDARs in the Mammalian CNS.- Section III: Glutamatergic Synaptic Transmission.- 10 Morphological Characteristics of Glutamatergic Synapses in the Hippocampus.- 11 Glutamate-Mediated Synaptic Excitation of Cortical Interneurons.- 12 Physiology of Glutamatergic Transmission at Calyceal and Endbulb Synapses of the Central Auditory Pathway.- 13 Glutamate Transporters and Their Contributions to Excitatory Synaptic Transmission.- Section IV: Involvement of Glutamate Receptors and Transporters in Neurological Diseases.- 14 Glutamate-Mediated Excitotoxicity.- 15 Glutamate Transporter Dysfunction and Neuronal Death.- 16 NMDA Recepor Antagonists and Their Potential as Neuroprotective Agents.

/pdf/ionotropic-glutamate-receptors-in-the-cns-4nhtkrl9ms.pdf

Ionotropic glutamate receptors in the CNS

Expression of glutamate receptor subunits in α-motoneurons

Glutamate receptor editing in the mammalian hippocampus and avian neurons.

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Expression of glutamate receptor subunits in α-motoneurons

Glutamate receptor editing in the mammalian hippocampus and avian neurons.