Gene therapies that enhance hippocampal neuron survival after an excitotoxic insult are not equivalent in their ability to maintain synaptic transmission

Research shows that overexpression of cytoprotective genes can spare neuron s 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 hipp ocampal 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 overe xpression, spatial learning is spared by Glut-1, but not Bcl-2, We postulat ed that Glut-1 and Bcl-2 act differently to protect hippocampal function an d investigated the effects of vector overexpression on synaptic physiology after KA treatment. Three days after RA and vector delivery to the dentate gyrus, mossy fiber-CA3 (MF-CA3) population excitatory postsynaptic potentia ls (EPSPs) were recorded in vitro. In addition to producing a lesion in are a CA3, KA treatment reduced baseline MF-CA3 synaptic strength, posttetanic potentiation (PTP), and long-term potentiation (LTP). A similar reduction i n 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. Re sults indicate greater protection of MF-CA3 synaptic transmission with over expression of Glut-1 compared to Bcl-2 and suggest that not all neuroprotec tive gene therapy techniques are equivalent in their ability to spare funct ion. (C) 2000 Academic Press.