Sparing of neuronal function postseizure with gene therapy

Numerous studies have demonstrated that gene therapy interventions can prot ect neurons from death after neurological insults. In nearly all such studi es, however, "protection" consists of reduced neurotoxicity, with no demons trated 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 v ivo. However, the mediating mechanisms and consequences of the two interven tions 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 oxi dative facets. Most importantly, GT- but not Bcl-2-mediated protection pres erved hippocampal function as assessed spatial maze performance. Thus, gene therapeutic sparing of neurons from insult-induced death does not necessar ily translate into sparing of function.