Synapses are central to understanding cellular mechanisms underlying learning, memory, certain disease states and more broadly aspects of mental organization. As yet, identified mammalian central synapses have been largely inaccessible to mechanistic study. Inspired by recent success in establishing in vitro synaptically coupled neurons from the marine mollusc Aplysia mediating learning, this proposal seeks to apply the Aplysia dissociated cell culture technique to neonatal rat brain slices. In this way cultures will be made containing two or at most three cells identified by origin and type. Not only will such cultures permit simultaneous recordings from synaptically coupled cells, but they will have relevance to actual synapses in vivo. To complement the cell culture approach, novel ways of approaching slices will be pursued that offer the possibility of examining the same synapses with dual recordings closer to the undisturbed state. The thrust of the work focuses on learning and schizophrenia. Organizing questions are: (1) What are the cellular bases of long- term potentiation -- are the mechanisms pre or post-synaptic or both? (2) What are the characteristics of dopaminergic synaptic transmission? (3) How are dopaminergic synapses influenced by neuroleptics in the short and long term? (4) How might dopaminergic synapses and neuroleptics impact on long-term potentiation? Understanding long-term potentiation in cellular terms promises the ability to target specific pharmacologic agents so as to relate the phenomenon to memory and behavior. Likewise, more explicitly correlating the behavioral effects of neuroleptics drugs with their sites of synaptic action may bridge between neuronal mechanisms and psychosis.
