Distally directed dendrotoxicity induced by kainic Acid in hippocampal interneurons of green fluorescent protein-expressing transgenic mice.
Excitotoxicity, resulting from the excessive release of glutamate, is thought to contribute to a variety of neurological disorders, including epilepsy. Excitotoxic damage to dendrites, i.e., dendrotoxicity, is often characterized by the formation of large dendritic swellings, or "beads." Here, we show that hippocampal interneurons that express the neuropeptide somatostatin are highly vulnerable to the excitotoxic effects of the ionotropic glutamate receptor agonist kainate. Brief, focal iontophoretic application of kainate rapidly induced bead formation in dendrites of somatostatinergic interneurons that express green fluorescent protein (GFP) from mice of the transgenic line GIN (GFP-expressing inhibitory neurons). Surprisingly, beads often did not form at the site of kainate application or even in the dendritic segment to which kainate was applied; instead, dendritic beading occurred more distally, often encompassing all branches distal to the application site. We have termed this phenomena, "distally directed dendrotoxicity." Distally directed beading was induced regardless of the branch order of the site of application and was found to be dependent on activation of voltage-gated sodium channels. Subsequent to induction, distally directed beading would reverse in most cells; in other cells, however, beading irreversibly invaded proximal dendritic segments and gradually encompassed the entire dendritic tree. These results demonstrate that distal dendritic segments are highly vulnerable to excitotoxic injury and imply that excessive excitatory activity originating in one synaptic pathway can impact synapses at more distal dendritic segments of the same neuron. The discovery of this phenomenon will likely be important in understanding interneuronal dysfunction following excitotoxic injury.
Oliva
Anthony A
AA
The Cain Foundation Laboratories, Division of Neuroscience, and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Lam
Trang T
TT
Swann
John W
JW
D000818:Animals; D019470:Biolistics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007478:Iontophoresis; D007608:Kainic Acid / Q000633:toxicity*; D008012:Lidocaine / Q000494:pharmacology; D008164:Luminescent Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013004:Somatostatin / Q000096:biosynthesis; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
D002121:Calcium Channel Blockers; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D013004:Somatostatin; D008012:Lidocaine; D007608:Kainic Acid