ECT-like brain stimulation triggers unexpected nuclear reprogramming in mature neurons

Nearly 90 years after Ugo Cerletti and Lucio Bini introduced electroconvulsive therapy (ECT), brain stimulation therapies such as ECT and Repetitive Transcranial Magnetic Stimulation (rTMS) are common in psychiatry because they are highly effective for treating depression and schizophrenia, yet their cellular mechanisms remain poorly understood. The team introduced REPOPS, a form of patterned stimulation in mice designed to mimic key features of ECT-like neuronal activation.

Mice subjected to REPOPS showed increased locomotor activity and reduced depression-like behavior, revealing stimulation-induced lasting behavioral changes similar to ECT-like states. At the cellular level, the stimulation induced a state of cellular dematuration, in which adult neurons had gene expression patterns resembling those seen in early postnatal development. Stimulation for three days caused only transient changes, while ten-day stimulation resulted in a stable dematuration state that persisted for over a month. Genome-wide chromatin mapping revealed widespread and persistent changes in chromatin accessibility, providing molecular evidence for the durability of this state. A reanalysis of postmortem brain RNA-seq data from patients with mood disorders showed that ECT-treated individuals exhibited a similar immature-like gene expression pattern in the dentate gyrus compared to non-ECT-treated patients, suggesting that similar immature-like changes may also occur in the human dentate gyrus after ECT.

Surprising emergence of cell cycle re-entry in mature neurons

A gene expression analysis revealed an unexpected finding: despite being post-mitotic (cells that no longer divide), neurons following REPOPS exhibited gene expression patterns characteristic of the G2/M phase of the cell cycle in dividing cells, accompanied by nuclear hallmarks of mitosis - histone phosphorylation, disruption of the nuclear lamina, and chromatin condensation. These molecular and structural changes suggested nuclear reprogramming. Using genome-editing technology, the researchers demonstrated that mice lacking Cyclin B, a key molecular regulator of the G2/M phase transition, showed less nuclear reprogramming and behavioral changes, identifying it as a driver of cellular state triggered by neuronal stimulation.

An intermediate state of heightened plasticity

The researchers next asked how nuclear reprogramming affects neuronal function. They used microscopic imaging of calcium fluxes, a proxy for neuronal activity, in behaving mice. Curiously, REPOPS did not simply turn neuronal activity on or off. Instead, it produced a patterned shift in how neurons encode different types of information - spatial coding was suppressed while speed-related coding was enhanced - that persisted for over two weeks.

Taken together, these molecular, nuclear structural, and functional findings led the researchers to propose that the dematured cellular state induced by ECT-like stimulation represents an "intermediate state" of high plasticity - neither the normal mature state nor the fully immature one - where the specific configuration may depend on how strongly, how often, and under what conditions neuronal activity is applied. The plasticity supporting therapeutic effects in depression could, under different conditions such as epilepsy or neurodegeneration, contribute to pathology instead.

Nuclear reprogramming - the ability of neurons to fundamentally reshape their own identity - is a candidate mechanism we had not previously considered. These findings provide a new cellular framework for thinking about how durable changes in neural function can arise, and they offer a potential route to improved therapies."

Prof. Tsuyoshi Miyakawa, Fujita Health University