Date of Award

Winter 1986

Project Type


Program or Major


Degree Name

Doctor of Philosophy


Recent evidence indicates that the activation of a calcium-dependent proteinase, calpain, results in the formation of new glutamate receptors in the hippocampus (Lynch, Halpain, & Baudry, 1982), a brain area commonly thought to play a crucial role in mammalian memory formation. In vitro, this effect is correlated with a long-lasting enhancement of efficacy in synaptic transmission (long-term potentiation, LTP) following brief pulses of electrical stimulation in the hippocampus (Dunwiddie & Lynch, 1979). Because the induction properties of LTP are similar to the behavioral properties of memory, it has been proposed to be the physiological basis of memory (Lynch & Baudry, 1984). If the calcium-dependent activation of calpain is responsible for the induction of LTP and ultimately memory formation, then pharmacologically blocking the calcium-calpain interactions should block those forms of memory dependent on this mechanism.

Three experiments were conducted to assess the effects of leupeptin, a proteinase (calpain) inhibitor on aversively motivated spatial memory in rats. In Experiment One, either leupeptin (8 mg/ml isotonic saline) or isotonic saline was infused continuously into the cerebrospinal fluid, and rats were trained in a one-way avoidance task with one-hour intertrial intervals, three trials per day, for 11 days. Leupeptin significantly impaired rats' acquisition of this task. Experiment Two assessed rats' performance in a win-stay or a win-shift avoidance task, and it was found that rats in the win-shift group learned the task more efficiently. This win-shift avoidance task was then used in Experiment Three to assess the temporal dependence of leupeptin's behavioral effects by introducing a delay of 1 min, 15 min, or 30 min between the information and choice trials. Leupeptin impaired choice performance at the 30 min delay only. In addition, leupeptin significantly impaired previously-acquired avoidance responding. Because a time-dependent memory deficit was observed, these data are considered to be consistent with the biological model of memory formation advanced by Lynch & Baudry (1984), however no adequate explanation of leupeptin's deleterious effects on previously acquired responding presently exists.