Excitotoxicity mediated by non-NMDA receptors causes distal axonopathy in long-term cultured spinal motor neurons.
Excitotoxicity has been implicated as a potential cause of neuronal degeneration in amyotrophic lateral sclerosis (ALS). It has not been clear how excitotoxic injury leads to the hallmark pathological changes of ALS, such as the abnormal accumulation of filamentous proteins in axons. We have investigated the effects of overactivation of excitatory receptors in rodent neurons maintained in long-term culture. Excitotoxicity, mediated principally via non-N-methyl-D-aspartate (NMDA) receptors, caused axonal swelling and accumulation of cytoskeletal proteins in the distal segments of the axons of cultured spinal, but not cortical, neurons. Axonopathy only occurred in spinal neurons maintained for 3 weeks in vitro, indicating that susceptibility to axonal pathology may be related to relative maturity of the neuron. Excitotoxic axonopathy was associated with the aberrant colocalization of phosphorylated and dephosphorylated neurofilament proteins, indicating that disruption to the regulation of phosphorylation of neurofilaments may lead to their abnormal accumulation. These data provide a strong link between excitotoxicity and the selective pattern of axonopathy of lower motor neurons that underlies neuronal dysfunction in ALS.
King
A E
AE
NeuroRepair Group, Menzies Research Institute, Hobart, Tasmania 7000, Australia.
Dickson
T C
TC
Blizzard
C A
CA
Foster
S S
SS
Chung
R S
RS
West
A K
AK
Chuah
M I
MI
Vickers
J C
JC
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects*; D016202:N-Methylaspartate / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D051381:Rats; D017470:Receptors, Glutamate / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D017470:Receptors, Glutamate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007608:Kainic Acid