Chronic electroconvulsive shock disrupts hippocampal physiology and impairs associative memory in mice

Abstract

Electroconvulsive therapy (ECT) is a highly effective treatment for depression but it has undesirable side effects on various aspects of cognition, including memory. Patients might display retrograde amnesia for autobiographical events and anterograde amnesia in tests of recall and recognition memory. These amnestic effects are likely to depend, at least in part, on changes in the hippocampus. ECT-induced volume increases in the hippocampus, and dentate gyrus subregion in particular, correlate with the cognitive deficits. However, the precise cellular and behavioral effects of ECT remain poorly understood. Here, we therefore subjected male and female mice to chronic electroconvulsive shock (ECS) and examined effects on hippocampal physiology and memory. Perforant path inputs onto dentate gyrus neurons were examined using whole cell patch clamp recordings in hippocampal slices. In the intact slice, perforant path stimulation did not result in any synaptic or spiking differences in mice given sham vs ECS treatments. However, GABAA blockade increased depolarization and spiking in sham, but not ECS-treated, mice. Voltage clamp recordings further revealed weaker perforant path excitation of dentate gyrus neurons in ECS-treated mice. Extrapolating these findings to the intact animal, we then used Fos expression as a proxy for neural activity, and found that ECS blunted exploration-induced hippocampal activation, which was most pronounced in the dentate gyrus. Finally, recognition memory tasks revealed that ECS impaired memory for object-context associations but not memory for objects or locations. Collectively, these experiments reveal that a clinically relevant schedule of ECS disrupts synaptic and circuit functions of the hippocampus and causes anterograde amnesia in a test of episodic-like associative memory.