Electroconvulsive stimulation and hippocampal synaptic plasticity
Electroconvulsive therapy (ECT) is a safe and effective treatment of severe depressive illness. Although it has now been used for over five decades, the mechanism of action remains unknown. A major side effect of ECT is a transient disturbance of memory. These factors have limited the acceptability and use of ECT. Detailed examination of the neurobiological effects of ECT may lead not only to the refinement of treatment but also to a better understanding of the disease that ECT treats so effectively. In recent years, many investigations into the neurobiology of memory have focused on an electrophysiological phenomenon known as long-term potentiation (LTP). LTP is an experimentally induced form of synaptic plasticity which can be readily demonstrated in the hippocampus and consititutes a long-lasting increase in synaptic strength. It has been proposed as a candidate mechanism for the neural substrate of learning. The aim of this thesis is to examine the effects of repeated ECS on this form of synaptic plasticity. Electrophysiological experiments demonstrate that repeated, spaced ECS causes a profound enhancement of the dentate gyms field response to stimulation of the perforant path afferent fibres in vivo and reduces the ability of this synaptic pathway to support experimentally induced LTP. A single ECS is not sufficient to produce this effect. Measurement of field potentials in unanaesthetised animals reveals that the increase in EPSP slope developes incrementally over the course reaching a maximum after five seizures. The effect of repeated ECS on synaptic plasticity is long-lasting but ultimately reversible as LTP can be induced, to within control levels, 40 days but not 10 days after the last treatment. The administration of ketamine (an NMDA receptor antagonist) for anaesthesia during ECS is shown to prevent the enhancement of the EPSP and impairment of LTP. In behavioural studies, repeated ECS significantly impairs spatial learning in the watermaze as measured by a consistent increase in escape latencies which is accompanied in one experiment by decreased searching in the vicinity of the platform during a retention test. The increase in escape latencies is prevented by the administration of ketamine anaesthesia during ECS in the same animals in which prevention of the effects on synaptic plasticity can be demonstrated These findings suggest that the profound but reversible impact of ECS on hippocampal LTP may account for the memory impairment described after electroconvulsive Stimulation in humans and other species. Ketamine, which reduces the impact of seizures on this process, may protect against ECS-induced memory impairment and thus prove useful in alleviating the transient cognitive impairment following ECT in humans.