A well-motivated and common working hypothesis is that learning involves some change in the functional connectivity among nerve cells, probably at their synaptic interconnections. In searching for a likely synaptic candidate for such changes in the mammalian central nervous system (CNS), the phenomenon of associative long-term potentiation (LTP) is an obvious choice, for three reasons: associative LTP is an increased synaptic efficacy that can be induced by brief tetanic stimulation; it lasts hours or longer; and the conditions required for its induction bear a tantalizing similarity to some of the laws of classical conditioning. The fact that associative LTP occurs in the in vitro hippocampus is extremely important because this is the only known mammalian telencephalic preparation that is amenable to many of our most powerful analytical neurophysiological techniques and in which a promising synaptic model for associative memory has been demonstrated. In the present proposal I will use the in vitro hippocampus slice preparation to investigate four key aspects of associative LTP. First, the spatial and temporal rules governing the induction of associative LTP will be elucidated. Second, certain conditions that control the persistence or rate of decay of associative LTP will be analyzed, paying particular attention to possible parallels to the extinction phenomenon seen in classical conditioning studies. Third, the basis of the change responsible for the enhanced synaptic efficacy will be determined. Specifically, I want to know whether the ultimate change is pre- and/or postsynaptic. Fourth, I will provide evidence about the key features underlying the mechanisms responsible for the associativity. In particular, I want to determine which consequences of the associative paradigm are causally instrumental in the induction of the enhancement.
