Glial cells and neurons show a different spatiotemporal excitability, and distinctively regulate brain functions. Glial cells, especially astrocytes, have very thin and fine processes, by which they communicate with neurons and glial cells. Due to such thin structure, the function of these fine processes could not be detected. Shigetomi et al. discovered membrane - associated Ca2+ probes, i. e. , Lck - GCaMP3, and visualized Ca2+ excitability there. Using this Ca2+ probes, we found that ischemic tolerance is dependent on astrocytic excitability. Ischemic tolerance is well - known event, by which the brain acquires resistance against brain ischemia. Due to its strong brain protective actions, there have been many lines of literature about ischemic tolerance. However, almost all such researches just focused on neurons. Preconditioning (PC) enhanced Ca2+ excitability in astrocytes, which could be obser ved only when we used the new Ca2+ indicator. PC upregulated P2X7 receptor, one of ATP receptor/channel, in astrocytes, and the astrocytic P2X7 receptor could function as a switch and/or trigger for formation of astrocyte- mediated ischemic tolerance.

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While an imaging technique by two- photon or multi- photon excitation fluorescence microscopy to depict, for example, a microglial process in the micron order is referred as an in vivo imaging of microglia, in vivo molecular imaging of microglia may be defined as a technique that enables to illustrate microglial activation by tagging a specific tracer on the proteins that develop in microglial cells during their activation. The latter method is advantageous in terms of no invasiveness to the brain and easy applicability to the human despite far lower spatial resolution than the in vivo imaging. In this article, neuroinflammation - related brain pathophysiology in dementia and neuropsychiatric disorders is described by citing the findings from positron emission tomography (PET) or a first- runner in vivo molecular imaging method using translocator protein (TSPO) tracers.

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Microglia, glial cells with immunological/inflammatory functions, have been suggested to play important roles in various psychiatric disorders. To clarify these aspects, novel translational methods should be applied. We herein introduce two novel translational research approaches focusing on human microglia, in order to clarify the relationship between psychopathology and microglia. (1) We have recently conducted an economic game - rust game - to healthy young males with or without 4 - day- treatment of minocycline, an antibiotic with microglial inhibitory effects. Interestingly, minocycline suppressed personality - oriented and/or drive - oriented social behaviors (Watabe, Kato, et al, 2013). (2) Deeper physiological/pathological molecular mechanisms of human microglia have not been clarified due to technical and ethical issues (such as difficulties of human brain biopsy). We developed a novel technique to induce microglia- like cells (iMG) from human peripheral broods within 2 weeks (Ohgidani, Kato, et al, 2014). We believe that our novel translational approach will open the door to explore various unknown psychopathological aspects of human microglia in psychiatric disorders.

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Children with ASD and concomitant mitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders, and it therefore appears that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction are likely due to these mitochondrial disorders. Disruption of ATP synthesis alone may be related to impaired glutathione synthesis. The adenosine triphosphate (ATP) production/oxygen consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress. A decrease in total antioxidant capacity may account for ASD children who show core social and behavioral impairments without neurological and somatic symptoms.

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Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder, which is based on morphological abnormalities in the brain. Cognitive impairment is a core symptom of the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive γ- aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that decreased glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex result in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting morphological abnormalities, especially, GABA neurons and their activities. -817MA, a novel neurotrophic agent, ameliorates loss of PV- positive GABA neurons in the medial prefrontal cortex and reduction of gamma- band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, drugs with anti-oxidant effects, such as T-817MA, are likely to prevent the onset and/or progression of schizophrenia.

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The effectiveness of D-cycloserine (DCS) , an N-methyl-D-aspartate glutamate receptor partial agonist, and valproic acid (VPA) , a histone deacetylase inhibitor, in facilitating the extinction of conditioned fear has been explored in humans and animals. We confirmed whether DCS (100 mg) and VPA (400 mg) act in off-line fear extinction processes during sleep or waking, for further clinical application to anxiety disorders and posttraumatic stress disorder (PTSD). We performed two consecutive randomized, placebo controlled clinical trials in healthy humans. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively. The off-line fear extinction effect was observed not in simple recall after the extinction of coupled CS-US, but was observed in the post-re-exposure phase after unexpected re-exposure to reinstatement CS-US coupling. In addition, VPA facilitated the off-line learning process of conditioned fear extinction during sleep, while DCS did during waking. These findings suggest that DCS and VPA might enhance exposure-based cognitive therapy for anxiety disorders and PTSD by reducing the vulnerability to reinstatement and preventing relapses of conditioned fear, and provide evidence for a peculiarity of the sleep-dependent off-line process for conditioned fear extinction.

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