title: Gene therapies that enhance hippocampal neuron survival after an excitotoxic insult are not equivalent in their ability to maintain synaptic transmission.
abstract: Research shows that overexpression of cytoprotective genes can spare neurons from necrotic death, but few studies have addressed the functional status of surviving neurons. Overexpression of a brain glucose transporter, Glut-1, or the anti-apoptotic protein, Bcl-2, in rats decreases the size of hippocampal lesions produced by kainic acid (KA) treatment. In animals in which KA-induced lesions are reduced to similar extents by Glut-1 or Bcl-2 overexpression, spatial learning is spared by Glut-1, but not Bcl-2. We postulated that Glut-1 and Bcl-2 act differently to protect hippocampal function and investigated the effects of vector overexpression on synaptic physiology after KA treatment. Three days after KA and vector delivery to the dentate gyrus, mossy fiber-CA3 (MF-CA3) population excitatory postsynaptic potentials (EPSPs) were recorded in vitro. In addition to producing a lesion in area CA3, KA treatment reduced baseline MF-CA3 synaptic strength, posttetanic potentiation (PTP), and long-term potentiation (LTP). A similar reduction in the KA-induced lesion was produced by overexpression of Glut-1 or Bcl-2. Glut-1, but not Bcl-2, attenuated the impairments in synaptic strength and PTP. Overexpression of Glut-1 or Bcl-2 preserved LTP after KA treatment. Results indicate greater protection of MF-CA3 synaptic transmission with overexpression of Glut-1 compared to Bcl-2 and suggest that not all neuroprotective gene therapy techniques are equivalent in their ability to spare function.
authors.affiliation: Department of Biological Sciences, Stanford University, Stanford, California 94305, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Dumas
authors.forename: J R
authors.initials: JR
authors.lastname: McLaughlin
authors.forename: D Y
authors.initials: DY
authors.lastname: Ho
authors.forename: M S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: R M
authors.initials: RM
authors.lastname: Sapolsky
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics*; D002863:Chromogenic Compounds; D018891:Dentate Gyrus / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D051272:Glucose Transporter Type 1; D006624:Hippocampus / Q000293:injuries / Q000473:pathology / Q000503:physiopathology*; D007608:Kainic Acid / Q000009:adverse effects; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D009498:Neurotoxins / Q000009:adverse effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002863:Chromogenic Compounds; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; C495679:Slc2a1 protein, rat; C090468:TP53BP2 protein, human; D007608:Kainic Acid