Effects of electroconvulsive shock on the function, circuitry, and transcriptome of dentate gyrus granule neurons

Abstract

Therapeutic use of electroconvulsive shock (ECS) is particularly effective for treatment-resistant depression. Like other more common forms of antidepressant treatment such as SSRIs, ECS has been shown to increase neurogenesis in the hippocampal dentate gyrus of rodent models. Yet the question of how ECS-induced neurogenesis supports improvement of depressive symptoms remains unknown. Here, we show that ECS-induced neurogenesis is necessary to improve depressive-like behavior of mice exposed to chronic corticosterone (Cort). We then use slice electrophysiology to show that optogenetic stimulation of adult-born neurons produces a greater hyperpolarization in mature granule neurons after ECS vs Sham treatment. We identify that this hyperpolarization requires the activation of group II metabotropic glutamate receptors. Consistent with this finding, we observe reduced expression of the immediate early gene cFos in the granule cell layer of ECS vs Sham subjects. Using single nucleus RNA sequencing, we reveal major transcriptomic shifts in granule neurons after treatment with ECS+Cort or fluoxetine+Cort vs Cort alone. We identify a population of immature cells which has greater representation in both ECS+Cort and fluoxetine+Cort treated samples vs Cort alone. We also find global differences in ECS-vs fluoxetine-induced transcriptomic shifts. Together, these findings highlight a critical role for immature granule cells in the antidepressant action of ECS.