Kainic acid induces early and delayed degenerative neuronal changes in rat spinal cord

Hugon, Jacques; Vallat, Jean‐Michel; Spencer, Peter S.; Leboutet, M. J.; Barthe, D

doi:10.1016/0304-3940(89)90585-5

Cited by 90 publications

(38 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Present results suggesting that cultured motor neurons are highly vulnerable to rapidly triggered AMPA /kainate receptor-mediated injury are in general agreement with previous studies of the excitotoxic vulnerability of motor neurons carried out in slice cultures (Rothstein et al, 1993;Rothstein and Kuncl, 1995) or animal models (Hugon et al, 1989b). Thus, motor neurons seem to maintain critical features pertinent to their excitotoxic vulnerability when transplanted into a dissociated culture system, suggesting that this simplified system may be useful for studying their vulnerability under controlled conditions.…”

Section: Excitotoxic Vulnerability Of Cultured Motor Neuronssupporting

confidence: 91%

“…First, three syndromes with prominent motor system manifestations, i.e., lathyrism (Spencer et al, 1986), domoic acid toxicity (Teitelbaum et al, 1990), and BMAA toxicity , are all linked to the consumption of environmental AMPA /kainate receptor agonists Bridges et al, 1989;Debonnel et al, 1989;Richter and Mena, 1989;Weiss et al, 1989). Second, motor neurons are injured preferentially by intrathecal kainate (Hugon et al, 1989b), and selective AMPA /kainate receptor antagonists protect motor neurons against degeneration caused by chronic blockade of glutamate uptake in spinal cord slice (Rothstein et al, 1993).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

1996

View full text Add to dashboard Cite

The nonphosphorylated neurofilament marker SMI-32 stains motor neurons in spinal cord slices and stains a subset of cultured spinal neurons neurons"], which have a morphology consistent with motor neurons identified in vitro: large cell body, long axon, and extensive dendritic arborization. They are found preferentially in ventral spinal cord cultures, providing further evidence that large SMI-32(ϩ) neurons are indeed motor neurons, and SMI-32 staining often colocalizes with established motor neuron markers (including acetylcholine, calcitonin gene-related peptide, and peripherin). Additionally, choline acetyltransferase activity (a frequently used index of the motor neuron population) and peripherin(ϩ) neurons share with large SMI-32(ϩ) neurons an unusual vulnerability to AMPA /kainate receptor-mediated injury. Kainateinduced loss of these motor neuron markers is Ca 2ϩ -dependent, which supports a critical role of Ca 2ϩ ions in this injury. Raising extracellular Ca 2ϩ exacerbates injury, whereas removal of extracellular Ca 2ϩ is protective. A basis for this vulnerability is provided by the observation that most peripherin(ϩ) neurons, like large SMI-32(ϩ) neurons, are subject to kainate-stimulated Co 2ϩ uptake, a histochemical stain that identifies neurons possessing Ca 2ϩ -permeable AMPA /kainate receptor-gated channels. Finally, of possibly greater relevance to the slow motor neuronal degeneration in diseases, both large SMI-32(ϩ) neurons and peripherin(ϩ) neurons are selectively damaged by prolonged (24 hr) low-level exposures to kainate (10 M) or to the glutamate reuptake blocker L-transpyrrolidine-2,4-dicarboxylic acid (100 M). During these lowlevel kainate exposures, large SMI-32(ϩ) neurons showed higher intracellular Ca 2ϩ concentrations than most spinal neurons, suggesting that Ca 2ϩ ions are also important in this more slowly evolving injury.

show abstract

Section: Excitotoxic Vulnerability Of Cultured Motor Neuronssupporting

confidence: 91%

mentioning

confidence: 99%

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

1996

View full text Add to dashboard Cite

show abstract

“…Although NMDA receptors likely contribute critically to neuronal injury in various acute conditions, several observations support the hypothesis that AM PA / kainate receptors may be of greater importance to the neurodegenerative process seen in AL S. First, three syndromes with prominent motor system manifestations, lathyrism (Spencer et al, 1986), domoic acid toxicity (Teitelbaum et al, 1990), and ␤-N-methylamino-L-alanine toxicity , are linked to the consumption of AMPA / kainate receptor agonists found in the environment Bridges et al, 1989;Debonnel et al, 1989;Weiss et al, 1989). In addition, kainate exposures preferentially injure motor neurons both in vivo (Hugon et al, 1989b) and in vitro (Carriedo et al, 1995(Carriedo et al, , 1996, and AMPA/kainate receptor antagonists protect against motor neuron degeneration caused by chronic blockade of glutamate uptake in both spinal cord slice cultures (Rothstein et al, 1993) and dissociated cultures (Carriedo et al, 1996).…”

mentioning

confidence: 59%

AMPA Exposures Induce Mitochondrial Ca²⁺Overload and ROS Generation in Spinal Motor NeuronsIn Vitro

Carriedo

Sensi²,

Yin³

et al. 2000

J. Neurosci.

287

204

View full text Add to dashboard Cite

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 2ϩ -permeable AMPA/kainate channels, which may permit rapid Ca 2ϩ 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 2ϩ loading in motor neurons, as indicated by a sharp increase in intracellular Ca 2ϩ after addition of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl hydrazone (FCCP) after the agonist exposure. The same exposures caused little mitochondrial Ca 2ϩ 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 Ϫ ) that block mitochondrial Ca 2ϩ uptake attenuated AMPA/kainate receptor-mediated motor neuron injury, suggesting that the mitochondrial Ca 2ϩ uptake and consequent ROS generation are central to the injury process.

show abstract

“…First, MNs are unusually sensitive to injury mediated through AMPA/kainate type glutamate receptors (Carriedo et al, 1995;Carriedo et al, 1996;Hugon et al, 1989;, and blockers of these receptors protect MNs from injury caused by prolonged blockade of glutamate uptake (Carriedo et al, 1996;Rothstein et al, 1993).…”

mentioning

confidence: 99%

Intrathecal infusion of a Ca2+-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS

Yin

Tang

Weiss

2007

Experimental Neurology

View full text Add to dashboard Cite

Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca 2+ permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca 2+ overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 d) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham treated G93A animals, 30 day NAS infusions (starting at 67 ±2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes.

show abstract

Kainic acid induces early and delayed degenerative neuronal changes in rat spinal cord

Cited by 90 publications

References 15 publications

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

AMPA Exposures Induce Mitochondrial Ca²⁺Overload and ROS Generation in Spinal Motor NeuronsIn Vitro

Intrathecal infusion of a Ca2+-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS

Contact Info

Product

Resources

About

Kainic acid induces early and delayed degenerative neuronal changes in rat spinal cord

Cited by 90 publications

References 15 publications

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

AMPA Exposures Induce Mitochondrial Ca2+Overload and ROS Generation in Spinal Motor NeuronsIn Vitro

Intrathecal infusion of a Ca2+-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS

Contact Info

Product

Resources

About

AMPA Exposures Induce Mitochondrial Ca²⁺Overload and ROS Generation in Spinal Motor NeuronsIn Vitro