Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia.
The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression.
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Hiroko
H
Nomaru
Kunihiko
K
Sakumi
Atsuhisa
A
Katogi
Yoshinori N
YN
Ohnishi
Kosuke
K
Kajitani
Daisuke
D
Tsuchimoto
Eric J
EJ
Nestler
Yusaku
Y
Nakabeppu
D017398:Alternative Splicing; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D015850:Interleukin-6 / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism*; D012640:Seizures / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D018690:Excitatory Amino Acid Agonists; D015850:Interleukin-6; D007608:Kainic Acid; D008840:Microfilament Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; C491049:Aif1 protein, mouse; C000591759:C5ar1 protein, mouse; C000594938:C5ar2 protein, mouse; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C483819:Fosb protein, mouse; C577686:interleukin-6, mouse
AP-1 transcription factors; kainic acid; neuroinflammation