Potassium channel gene therapy can prevent neuron death resulting from necrotic and apoptotic insults.
Necrotic insults such as seizure are excitotoxic. Logically, membrane hyperpolarization by increasing outwardly conducting potassium channel currents should attenuate hyperexcitation and enhance neuron survival. Therefore, we overexpressed a small-conductance calcium-activated (SK2) or voltage-gated (Kv1.1) channel via viral vectors in cultured hippocampal neurons. We found that SK2 or Kv1.1 protected not only against kainate or glutamate excitotoxicity but also increased survival after sodium cyanide or staurosporine. In vivo overexpression of either channel in dentate gyrus reduced kainate-induced CA3 lesions. In hippocampal slices, the kainate-induced increase in granule cell excitability was reduced by overexpression of either channel, suggesting that these channels exert their protective effects during hyperexcitation. It is also important to understand any functional disturbances created by transgene overexpression alone. In the absence of insult, overexpression of Kv1.1, but not SK2, reduced baseline excitability in dentate gyrus granule cells. Furthermore, while no behavioral disturbances during spatial acquisition in the Morris water maze were observed with overexpression of either channel, animals overexpressing SK2, but not Kv1.1, exhibited a memory deficit post-training. This difference raises the possibility that the means by which these channel subtypes protect may differ. With further development, potassium channel vectors may be an effective pre-emptive strategy against necrotic insults.
Lee
Angela L
AL
Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA. angelee@stanford.edu
Dumas
Theodore C
TC
Tarapore
Phiroz E
PE
Webster
Brian R
BR
Ho
Dora Y
DY
Kaufer
Daniela
D
Sapolsky
Robert M
RM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D051662:Kv1.1 Potassium Channel; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels; D012966:Sodium Cyanide / Q000633:toxicity
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; C496899:Kcnn2 protein, rat; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D051662:Kv1.1 Potassium Channel; D012966:Sodium Cyanide