Brain-derived neurotrophic factor induces sustained elevation of intracellular Ca2+ in rodent microglia.
Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, 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. In this study, we observed that BDNF induced a sustained increase in [Ca(2+)]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosin-related kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry 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, pretreatment of BDNF suppressed the IFN-gamma-induced increase in [Ca(2+)]i, along with a rise in basal levels of [Ca(2+)]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.
Mizoguchi
Yoshito
Y
Department of Neuropsychiatry, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Monji
Akira
A
Kato
Takahiro
T
Seki
Yoshihiro
Y
Gotoh
Leo
L
Horikawa
Hideki
H
Suzuki
Satoshi O
SO
Iwaki
Toru
T
Yonaha
Miyuki
M
Hashioka
Sadayuki
S
Kanba
Shigenobu
S
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D010738:Type C Phospholipases / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D011994:Recombinant Proteins; C109458:r-metHuBDNF protein, recombinant; D020813:Receptor, trkB; D010738:Type C Phospholipases; D002118:Calcium