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22on the results of magnetic resonance spectroscopy in bipolar disorder patients showing impaired energy metabolism and high levels of mitochon-drial DNA (mtDNA) mutations in postmortem brains of patients. It has been reported that patients with mitochondrial diseases have a high rate of bipolar disorder (around 20%)24).Therefore, we created transgenic mice that express a mutant of polymerase gamma (Polg, mtDNA synthetase), one of the genes responsible for mitochondrial disease, only in the brain. The mice exhibited recurrent hypoactive episodes that lasted about two weeks25). This condition occurred on average once every six months, and detailed behavioral analysis showed that they met the diag-nostic criteria for a depressive episode (loss of interest, sleep disturbance, increased appetite, slow movements, fatigability, and impaired social behavior). During lithium treatment, these episodes became less frequent, and the patients showed increased corticosteroids during the episodes. In addition, tricyclic antidepressants caused manic-like behav-ioral changes.To clarify the brain region responsible for this hypoactivity, we searched for brain regions with high accumulation of mtDNA mutations and found the highest accumulation in the paraventricular thalamic nucleus (PVT). When we manipulated the neuronal circuits of the PVT in mice, similar hypo-active episodes appeared, suggesting that the depression in the model mice was caused by dysfunction of the PVT.The PVT receives strong projections from sero-tonergic neurons and is a brain region with high serotonin concentration. It is unique in that it proj-ects to both the amygdala, which is involved in the fear, negative emotion and the nucleus accumbens, which is involved in the reward, positive emotion26).In another mouse model of mitochondrial disease (Ant1 mutant mice), serotonin neurons showed hyperexcitability27). Hyperexcitability also suggested in a study of neurons derived from induced pluripotent cells of patients with bipolar disorder28). Neurons in the PVT may also be hyper-excitable in the mutant POLG mice described above. If overexcitability of the serotonin neuron-PVT system is involved in the pathogenesis of bipolar disorder, we may be able to understand the patho-genesis of this disorder, which presents depressive is and manic states in which both negative and posi-tive emotions are extremely enhanced.These findings suggest the entire picture of bipolar disorder. Genomic factors result in impaired intracellular Ca2+ regulation, which leads to hyper-excitability of emotion-related neural circuits, resulting in impaired emotion/cognition balance11).The gene that regulates excitability in the PVT is a T-type Ca2+ channel, and valproic acid is known to be its inhibitor.Among the serotonin receptors, serotonin 5-HT7 receptors have a characteristic distribution of being abundant in the PVT29), and it is noteworthy that lurasidone is a blocker of serotonin 5-HT7 receptors.Mechanism of action of therapeutic agentsThe most common theory of the mechanism of action of lithium is inhibition of inositol monophos-phatase (IMPase). Inhibition of IMPase causes intracellular depletion of inositol, resulting in dimin-ished agonist-stimulated inositol phospholipid metabolism, which results in attenuation of intra-cellular Ca2+ mobilization. It is also suggested that GSK-3β inhibition also plays a role in lithium’s action. In a study that screened compounds that inhibit IMPase, a drug called ebselen was found, and recently it was suggested that ebselen may be effective in the manic state of bipolar disorder30), which may support the theory that the mechanism of action of lithium is via IMPase inhibition.On the other hand, for antiepileptic drugs, many attempts have been made to search for common effects with lithium, and intriguing results were obtained. However, no consensus has been reached. Recent genomic studies have found associations with genes involved in neuronal excitability, including Ca2+ channels, and iPS cells derived from bipolar disorder patients28), as well as our studies in animal models, have indicated hyperexcitability of neurons. It makes sense to think that these antiepi-leptic drugs are acting by modulating neuronal excitability, similarly to their action to epilepsy.Most antipsychotics antagonize the dopamine D2 receptor, which is thought to be the major mode of action for schizophrenia. Most antipsychotics are also effective in manic states, and their effects on manic states are also thought to be mediated by dopamine D2 receptor antagonism. Atypical anti-