Rapid and stable changes in maturation-related phenotypes of the adult hippocampal neurons by electroconvulsive treatment

Abstract

Electroconvulsive therapy (ECT) is a highly effective and fast-acting treatment for depression. Despite a long history of clinical use, its mechanism of action remains poorly understood. Recently, a novel cellular mechanism of antidepressant action has been proposed: the phenotype of mature brain neurons is transformed to immature-like one by antidepressant drug treatments. We show here that electroconvulsive stimulation (ECS), an animal model of ECT, causes profound changes in maturation-related phenotypes of neurons in the hippocampal dentate gyrus of adult mice. Single ECS immediately reduced expression of mature neuronal markers in almost entire population of dentate granule cells. After ECS treatments, granule cells showed some of physiological properties characteristic of immature granule cells such as higher somatic intrinsic excitability and smaller frequency facilitation at the detate-to-CA3 synapse. The rapid downregulation of maturation markers was suppressed by antagonizing glutamate NMDA receptors, but not by perturbing the serotonergic system. While single ECS caused short-lasting effects, repeated ECS induced stable changes in the maturation-related phenotypes lasting more than 2 weeks along with enhancement of synaptic excitation of granule cells. Augmentation of synaptic inhibition or blockade of NMDA receptors after repeated ECS facilitated regaining the initial mature phenotype, suggesting a role for endogenous neuronal excitation in maintaining the altered maturation-related phenotype probably via NMDA receptor activation. These results suggest that brief neuronal activation by ECS induces “dematuration” of the mature granule cells and that enhanced endogenous excitability is likely to support maintenance of such a demature state. The global increase in neuronal excitability accompanying this process may be relevant to the high efficacy of ECT.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0288-9) contains supplementary material, which is available to authorized users.

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus

“…; Imoto et al . ). It remains unknown whether ECS actually suppresses late maturation during adult neurogenesis.…”

“…We did not use official randomization methods because of the relatively small numbers of mice (3-8 mice per group) used. Bilateral ECS (current, 30 mA; shock duration, 1 s; frequency, 100 pulses/s; pulse width, 0.5 ms) was administered via moistened, spring-loaded ear-clip electrodes (Bioresearch Center, Nagoya, Japan), with a pulse generator (ECT Unit; Ugo Basile, Gemonio, Italy), to mice that were anesthetized with isoflurane (1.5-2%, Pfizer, Japan) in order to minimize their suffering and avoid sudden, unexpected death associated with seizures (Imoto et al 2017). The shock administered produced a tonic seizure phase, characterized by the extension of all 4 limbs, which lasted for more than 10 s. After 3 min, the animal returned to a normal physiological condition.…”

“…; Imoto et al . ). ECS rapidly reduces the expression of mature neuronal markers in the DG and increases somatic excitability, resembling the phenotype of immature neurons, suggesting that ECS could reverse the late maturation status in mature neurons.…”

“…In addition to the facilitation of neurogenesis in the DG, we recently demonstrated that the phenotype of mature granule cells in the DG is transformed to that of immaturelike cells by antidepressants such as SSRIs and ECS (Kobayashi et al 2010;Imoto et al 2017). ECS rapidly reduces the expression of mature neuronal markers in the DG and increases somatic excitability, resembling the phenotype of immature neurons, suggesting that ECS could reverse the late maturation status in mature neurons.…”

The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors

“…Furthermore, electroconvulsive stimulation in animals, which simulates electroconvulsive therapy (a highly effective and fast-acting treatment for depression) in people, rapidly induces dematuration changes in GCs (Imoto et al, 2017). Together, these data imply a degree of clinical relevance for these phenotypic changes in GCs.…”