Noradrenergic (NAergic) neurons in the locus coeruleus (LC) have been implicated in fear, anxiety, arousal, and stress. In addition, LC‐NAergic neurons are activated by peripheral noxious stimulation. These neurons project their axons to the brain regions but also to the spinal dorsal horn (SDH) , and it is believed that spinal NA suppresses pain transmission. Like the brain, numerous glial cells are present in the SDH. We have recently identified a subset of astrocytes localized in the superficial SDH and found that in response to noxious stimulation to the skin, this subset induces a rise in intracellular calcium levels. The astrocytic responses were mediated by signals from the descending LC‐NAergic neurons, resulting in causing behavioral hypersensitivity to light mechanical stimuli. This review describes the new astrocyte‐mediated regulatory mechanism in descending noradrenergic pain control.

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We examined the role of astrocytes in the molecular pathogenesis of depression based on the pharmacological effects of the SSRI‐type antidepressants fluoxetine (FLX) and ketamine on glial cells, especially astrocytes. In addition to inhibition of serotonin uptake, chronic administration of FLX had a role to enhance astrocytic ATP exocytosis and ATP receptor‐dependent BDNF production, resulting in antidepressant effects. On the other hand, ketamine, well‐known as a general anesthetic by inhibition of NMDA receptors, showed immediate and sustained antidepressant effects at concentrations lower than the anesthetic dose. The ketamine‐hypersensitive NMDA receptors are astrocyte‐specific, and ketamine produced immediate and sustained antidepressant effects by altering the plasticity of astrocytes through these receptors. Although they are completely different antidepressants, they share some common mechanisms of action by acting on astrocytes to normalize the neuro‐glial coupling. These results suggest that astrocytes may be a promising therapeutic target for depression.

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Stress due to severe environments causes emotional disturbances, including depression and anxiety, and increases the risk of depression and other mental illnesses. Chronic stress in mice induces proinflammatory cytokines in microglia of the medial prefrontal cortex and promotes depressive‐like behavior. Besides, chronic stress augments prostaglandin（PG）E₂ synthesis in subcortical regions through metabolizing neuron‐derived 2AG by COX1, a microglia‐expressing PG synthase, and promotes depressive‐like behavior via the EP1 receptor. This PGE₂ synthesis depends on TLR2/4. Chronic stress‐induced anxiety‐like behavior also depends on TLR2/4 and PGE₂‐EP1 pathway, but not on brain PGE₂ synthesis. As it has been suggested that chronic stress induces emotional changes with leukocyte mobilization, peripheral PGE₂ synthesis could be involved. These findings suggest that TLR2/4 orchestrates multiple inflammatory responses to chronic stress inside and outside the brain, thereby leading to depressive‐ and anxiety‐like behaviors.

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Microglia are immune cells in the brain, and microglia have recently been suggested to contribute to a variety of mental disorders. Herein, we introduce our novel reverse‐translational research system using peripheral bloods to clarify the underlying pathophysiology of microglial dysfunctions in mental disorders by analyzing plasma components (i. e. metabolomics) and by producing/analyzing induced microglia‐like (iMG) cells from monocytes. In this paper, we introduce our latest research especially focusing on plasma metabolomic analysis in patients with major depressive disorder.

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Recent positron emission tomography studies have revealed glial activation in endogenous psychiatric disorders, such as schizophrenia and major depression, suggesting that the involvement of glial cells in the pathophysiology of these disorders. In fact, the decreased coverage of brain blood vessels by astrocytic endfeet has been identified in postmortem brains of major depression patients. Although electroconvulsive treatment (ECT) is regarded as an efficient treatment for refractory schizophrenia and major depression, its therapeutic mechanism is still unknown. The author’s group has already shown that antidepressants as well as antipsychotics inhibit microglial activation in vitro. Using pathognomonic rats called Gunn rats, which show congenital activation of microglia and astrocytes and exert both depressive‐like and schizophrenia‐like behavior, we have recently demonstrated that ECT attenuates activated astrocytic in addition to activated microglia with amelioration of their abnormal behavior. In addition, ECT has been demonstrated to significantly restore the decreased coverage of blood vessels by astrocytic endfeet in the hippocampus and prefrontal cortex of Gunn rats. These findings suggest that the therapeutic effects of ECT is exerted through the inhibition of activated microglia and astrocytes, and the restoration of impaired gliovascular units. Accordingly, glia can be considered as new promising targets for therapeutic actions of electroconvulsive treatment.

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Microglia are the primary cells responsible for neuroimmune. The roles of microglia include phagocytosis, scavenging, the release of cytokines, and antigen presentation to T cells. Furthermore, microglia help to form efficient neural circuits by removing excess neurons and synapses during neurodevelopment. After maturity, microglia also have an essential role in memory formation and elimination by using a complement‐dependent system. In degenerative diseases such as Alzheimer’s disease, microglia have the capacity to clean pathological changes like amyloid‐β and abnormal tau protein. Moreover, microglia attack and remove normal neurons and synapses, resulted in cognitive decline. In patients with Alzheimer’s disease, synaptic pathology and abnormalities of presynaptic proteins were reported. The reductions of presynaptic proteins were associated with cognitive declines in the patients. Presynaptic proteins, complexin‐1, mainly distributed in inhibitory neurons, were reported to be associated with cognitive functions in early dementia. Complexin‐2, dominantly distributed in excitatory nerves, was shown to be correlated with cognitive functions during the progression of dementia. We plan to evaluate the distribution of complexin and microglia by quantitative immunohistochemistry of older adults’ hippocampal tissues with and without dementia.

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As underlying pathological hypotheses of both depression and Alzheimer’s disease (AD) , neuroinflammation hypothesis and BDNF hypothesis are recently drawing attention. In addition, lifestyle‐related diseases such as diabetes and obesity are also involved in the pathogenesis of both depression and AD, indicating that it is very important to review daily lifestyles such as diet, exercise, and sleep to prevent and delay the onset of depression and AD. Moreover, activation of microglia is also involved in the pathophysiology of depression and AD. Recent reports suggest that microglial senescence as a new therapeutic target to protect and potentiate the function of residual microglia, including phagocytic activity of amyloid‐β (Aβ) .

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A viewpoint focusing on the interaction between neurons and glia is important for elucidating the pathophysiology and developing therapeutics in psychiatric disorders. We focus on glial cell line‐derived neurotrophic factor (GDNF) among the multiple neurotrophic factors stored in astrocytes, involved in mood disorder patients. Especially classical tricyclic antidepressants have been found to act directly on astrocytes and induce GDNF expression by a mechanism different from that of monoamines and acetylcholine. Furthermore, we found that the antidepressant target molecule is lysophosphatidic acid (LPA) receptor 1, which is one of the G protein‐coupled receptors of lysophospholipids. Tricyclic antidepressants are prototypes of antidepressants found by chance in the 1950s, and are still showing clinical efficacy over SSRIs and SNRIs in severe and refractory patients, and the high risk of manic change. Its pharmacological effects may be associated with potent antidepressant effects. In mouse brain, LPA1 receptor expression was different depending on the site and was localized to astrocytes and oligodendrocytes. In addition, the concentration of autotaxin (ATX) , which is an LPA synthase, was significantly decreased in the blood and cerebrospinal fluid of depressed patients, and was significantly correlated with the depressive symptoms and the course of treatment. Since LPA is associated with neurogenesis, angiogenesis and inflammation, and LPA1 receptor knockout mice exhibit depressive like behavior, the ATX/LPA/LPA1 receptor‐mediated lysophospholipid cascade is the potential to become a new molecular basis for the pathophysiology of mood disorders and develop therapeutics. No potential conflicts of interest were disclosed.

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Patients with psychiatric disorders, especially for schizophrenia, exhibit impairments in diverse cognitive functions, such as sensory processing, memory attention, learning, reasoning and executive function. Because of their refractory nature, there is an urgent need to develop effective treatments by identifying the neural mechanisms of cognitive dysfunction. In prefrontal cortex, a key driver in cognitive function, accumulating evidence have suggested that altered balance between excitatory and inhibitory networks play, at least in part, an essential role in the neural basis underlying cognitive impairments in psychiatric disorders. The authors believe identifying upstream factors and signaling cascades that cause functional changes in excitatory and inhibitory neurons in the prefrontal neural network should lead to understanding the pathophysiology and developing the treatment strategies. With these reasons in mind, this mini review will introduce our recent postmortem brain research focusing on dysregulated excitatory/inhibitory neural network activity in patients with psychiatric disorders.

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