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Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO) and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca 2+ concentration ([Ca 2+ ]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. We have recently reported that BDNF induces a sustained increase in [Ca 2+ ]i through binding with the truncated TrkB receptor, resulting in activation of the PLC pathway and store-operated calcium entry (SOCE) in rodent microglial cells. Sustained activation of SOCE, possibly mediated by TRP channels, occurred after brief BDNF application and contributed to the maintenance of sustained [Ca 2+ ]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, selective serotonin reuptake inhibitors (SSRIs), including paroxetine or sertraline, potentiated the BDNFinduced increase in [Ca 2+ ]i in rodent microglial cells This article provides a review of recent findings on the role of BDNF in the pathophysiology of neuropsychiatric disorders, especially by focusing on its effect on intracellular Ca 2+ signaling in microglial cells.

Schizophrenia is one of the most severe psychiatric diseases noted for its chronic and often debilitating processes; affecting approximately 1% of the worlds population, while its etiology and therapeutic strategies still remain elusive. In the 1950s, the discovery of antipsychotic effects of haloperidol and chlorpromazine shifted the paradigm of schizophrenia. These drugs proved to be antagonists of dopamine D2 receptor (D2R), thus dopamine system dysfunction came to be hypothesized in the pathophysiology of schizophrenia, and D2R antagonism against dopamine neurons has been considered as the primary therapeutic target for schizophrenia. In addition, abnormalities of glutamatergic neurons have been indicated in the pathophysiology of schizophrenia. On the other hand, recent neuroimaging studies have shown that not only dementia but also schizophrenic patients have a significant volume reduction of some specific regions in the brain, which indicates that schizophrenia may involve some neurodegenerative process. Microglia, major sources of various inflammatory cytokines and free radicals such as superoxide and nitric oxide (NO) in the CNS, play a crucial role in a variety of neurodegenerative diseases such as dementia. Recent postmortem and positron emission computed tomography (PET) studies have indicated that activated microglia may be present in schizophrenic patients. Recent in vitro studies have suggested the anti-inflammatory effects of antipsychotics on microglial activation. In this article, we review the anti-inflammatory effects of antipsychotics on microglia, and propose a novel therapeutic hypothesis of schizophrenia from the perspective of microglial modulation.