Sparing of neuronal function postseizure with gene therapy.
Numerous studies have demonstrated that gene therapy interventions can protect neurons from death after neurological insults. In nearly all such studies, however, "protection" consists of reduced neurotoxicity, with no demonstrated preservation of neuronal function. We used a herpes simplex virus-1 system to overexpress either the Glut-1 glucose transporter (GT) (to buffer energetics), or the apoptosis inhibitor Bcl-2. Both decreased hippocampal neuron loss to similar extents during excitotoxic insults in vitro and in vivo. However, the mediating mechanisms and consequences of the two interventions differed. GT overexpression attenuated early, energy-dependent facets of cell death, blocking oxygen radical accumulation. Bcl-2 expression, in contrast, blocked components of death downstream from the energetic and oxidative facets. Most importantly, GT- but not Bcl-2-mediated protection preserved hippocampal function as assessed spatial maze performance. Thus, gene therapeutic sparing of neurons from insult-induced death does not necessarily translate into sparing of function.
McLaughlin
J
J
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Roozendaal
B
B
Dumas
T
T
Gupta
A
A
Ajilore
O
O
Hsieh
J
J
Ho
D
D
Lawrence
M
M
McGaugh
J L
JL
Sapolsky
R
R
D000818:Animals; D002478:Cells, Cultured; D015316:Genetic Therapy; D051272:Glucose Transporter Type 1; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051381:Rats; D012640:Seizures / Q000628:therapy*; D013647:Task Performance and Analysis
D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495677:SLC2A1 protein, human; C495679:Slc2a1 protein, rat; D007608:Kainic Acid