NEUROTROPHIN MODULATION OF SYNAPTIC STRUCTURE

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The ability of the brain to alter information processing by changing the structure and strength of synaptic connections is essential for the successful development and survival of organisms. There is increasing evidence that the central nervous system utilizes some of the same molecular mechanisms during both developmental and adult plasticity. The neurotrophins are a class of signalling molecules that promote the growth and survival of distinct neuronal populations during the development of the nervous system. Our previous work demonstrated that two neurotrophins, BDNF and NT-3, but not NGF, can rapidly enhance synaptic transmission in the CA1 region of the adult rat hippocampus. An as yet unanswered question is whether the rapid changes in hippocampal synaptic transmission are accompanied or followed by structural synaptic changes in the adult animal. The results of many developmental studies highlight the enormous potential of the neurotrophins as signals which promote morphological changes during neuro- and synaptogenesis. We now propose to examine the effects of acute and long-term neurotrophin exposure on neuronal and synaptic morphology in living adult rat hippocampal neurons. To date, most studies have relied on retrospective examination of tissue treated with a neurotrophin or a pharmacological agent known to alter synaptic transmission. We will use two-photon scanning laser microscopy to examine dynamic changes in synaptic structure during and following the period of neurotrophin exposure. To examine the long-term effects of neurotrophin or Trk receptor overexpression on synaptic plasticity, we will use adenovirus(Ad) vectors containing cDNAs for these proteins. We will inject Ad-neurotrophin vectors into hippocampal tissue in vitro (slices) and in vivo. We will examine a variety of measures of synaptic transmission, synaptic structure and animal behavior. To further address the involvement of the neurotrophins in plasticity, we will also use dominant negative Trk constructs to test for effects on synaptic or behavioral plasticity.