In particular, it is unknown how distinct types of treatments, antidepressant drug medication and ECT, converge on the same antidepressant action. Despite a long history of clinical use, the mechanism of action of ECT still remains poorly understood. ECT has fast-acting antidepressant effects and is effective in most of medication-resistant patients. ECT was originally devised for treating psychosis in the 1930s and is currently considered as the most effective treatment for depression. In addition to antidepressant drugs, electroconvulsive therapy (ECT) has been used to treat depression. This proposal has been supported by demonstration of similar SSRI-induced changes in the neuronal maturation status in other brain regions. Therefore, we proposed that modifications of maturation-related phenotypes in mature neurons may cause some beneficial or therapeutic effects of SSRIs by reinstating cellular functions of immature neurons. In a mouse model of depression and anxiety, the changes in the maturation-related phenotypes of GCs can be induced at a serum concentration of fluoxetine close to that seen in patients during fluoxetine medication, suggesting clinical relevance of these changes in GCs. Such unstable and unpredictable nature of the effects of fluoxetine well mimics common clinical observations in antidepressant medication such as delayed emergence of therapeutic effects and treatment resistance. These changes in the maturation-related phenotypes of GCs were not observed after short-term treatment of fluoxetine, and the efficacy of fluoxetine is quite variable among individual mice. These changes cannot be explained simply by an increase in newly generated immature GCs, but are most likely characterized as “dematuration” of mature GCs. The fluoxetine treatment strongly reduced expression of mature GC markers, induced active somatic membrane properties resembling immature GCs, and decreased short-term plasticity at the dentate-to-CA3 synaptic connection that characterizes the mature dentate-to-CA3 signal transmission. We have recently demonstrated distinct changes in the molecular and physiological phenotypes of GCs as a candidate cellular mechanism of action of a selective serotonin reuptake inhibitor (SSRI): The SSRI fluoxetine can transform several mature features of GCs in the adult mouse DG. Granule cells (GCs) in the hippocampal dentate gyrus (DG) have been implicated in the pathophysiological mechanisms of neuropsychiatric disorders including depression and schizophrenia, and have been suggested to be an important target for both pharmacological and physical therapeutic treatments. The global increase in neuronal excitability accompanying this process may be relevant to the high efficacy of ECT.
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. 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. 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. The rapid downregulation of maturation markers was suppressed by antagonizing glutamate NMDA receptors, but not by perturbing the serotonergic system. 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. Single ECS immediately reduced expression of mature neuronal markers in almost entire population of dentate granule cells. 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. 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. Despite a long history of clinical use, its mechanism of action remains poorly understood. Electroconvulsive therapy (ECT) is a highly effective and fast-acting treatment for depression.