Neighbor effects of neurons bearing protective transgenes.
Viral vectors bearing protective transgenes can decrease neurotoxicity after varied necrotic insults. A neuron that dies necrotically releases glutamate, calcium and reactive oxygen species, thereby potentially damaging neighboring neurons. This raises the possibility that preventing such neuron death via gene therapy can secondarily protect neighboring neurons that, themselves, do not express a protective transgene. We determined whether such "good neighbor" effects occur, by characterizing neurons that, while uninfected themselves, are in close proximity to a transgene-bearing neuron. We tested two genes whose overexpression protects against excitotoxicity: anti-apoptotic Bcl-2, and a calcium-activated K(+) channel, SK2. Using herpes simplex virus type 2-mediated transgene delivery to hippocampal cultures, we observed "good neighbor" effects on neuronal survival following an excitotoxic insult. However, in the absence of insult, "bad neighbor" effects could also occur (i.e., where being in proximity to a neuron constitutively expressing one of those transgenes is deleterious). We also characterized the necessity for cell-cell contact for these effects. These phenomena may have broad implications for the efficacy of gene overexpression strategies in the CNS.
Lee
Angela L
AL
Department of Biology, Stanford University, Stanford, CA 94305-5020, USA. angelee@stanford.edu
Campbell
Laura B
LB
Sapolsky
Robert M
RM
D000818:Animals; D002450:Cell Communication; D002470:Cell Survival; D002478:Cells, Cultured; D015316:Genetic Therapy; D005822:Genetic Vectors; D018258:Herpesvirus 2, Human; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes
D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051640:Small-Conductance Calcium-Activated Potassium Channels