P3-7
構造的シナプス可塑性へのBDNF/proBDNF信号の関与：BDNF切断不全マウスによる追加証拠
櫻木 繁雄，冨永（吉野） 恵子，小倉 明彦
大阪大院・生命機能・神経可塑性生理学
We previously found in the stable cultures of the rodent hippocampus that repeated inductions of LTP and LTD lead to slowly developing long-lasting synaptic enhancement and suppression coupled with synapse formation and elimination, respectively. We call these structural synaptic plasticity phenomena RISE（repetitive LTP-induced synaptic enhancement）and LOSS（LTD-repetition-operated synaptic suppression）. Regarding RISE and LOSS as model systems suitable for the cell biological analyses of memory consolidation, we are analyzing the mechanisms underlying RISE and LOSS. By using function-blocking antibodies to neurotrophin receptors, we concluded that RISE is mediated by BDNF（brain derived neurotrophic factor）-TrkB signaling pathway, while LOSS is mediated by proBDNF（BDNF precursor）-p75NTR signaling pathway.
To obtain further support for this conclusion, we used here a transgenic mouse line which has a cleavage-resistant site in proBDNF protein and thus lacks mature BDNF（kindly provided by Dr. M. Kojima（AIST））. The hippocampal slice culture prepared from the homozygous transgenic mouse failed to produce RISE upon repeated application of forskolin（adenylate cyclase activator）. By the exogenous application of BDNF coupled with forskolin, RISE-like synaptic enhancement occurred, indicating that the culture is not devoid of the capability of synapse formation. The culture failed to produce LOSS upon repeated activation of metabotropic glutamate receptor, either. This is explained on account of the occlusion, since the magnitude of EPSP was already low. |
| P3-8
海馬興奮神経のシナプスの形成はTREM2とC1qの発現に依存する
大谷 嘉典，デイビス ディージャ，スロニオウスキー スラヲミル，ヘルナンデス アルフレッド，エーテル イリナ，カルソン モニカ
カリフォルニア大学リバーサイド校医学部生物医学研究科
Lack of a functional TREM2-DAP12 signaling pathway causes early onset cognitive dementia in humans evident by the third decade of life. Although the clinical presentation initially suggested a neuronal defect, we find that within the CNS, TREM2 expression is detected in microglia. The mutations in the ligand binding pocket of TREM2 are linked with increased risk for Alzheimer's and Frontal Temporal Lobe Dementia. Why does a defect TREM2 in microglia lead to neurologic disorder? In addition, Complement cascade components C1q and C3 were shown to be necessary for pruning of synapses by microglia during development. Therefore, we hypothesized microglial TREM2 and C1q would both regulate hippocampal synapse formation with normal development. Here using immunohistochemistry, we find that postnatal maturation of hippocampal vGlut1+ excitatory synapses is inhibited in TREM2 KO mice. Strikingly, the inhibition of the normal developmental increase in vGlut1+ synapses in unmanipulated TREM2 KO mice is similar to that observed in wild-type mice subjected to systemic inflammation during post-natal development. Because microglial stripping of synapses has been reported to be dependent on C1q, we tested whether inhibition of vGlut1+ synapse formation in both systemic inflammation initiated by intraperitoneal LPS injection and TREM2 KO mice was C1q dependent. We found that LPS but not TREM2 deficiency triggered inhibition of vGlut1+ synapse formation was C1q dependent. Taken together these data indicate that TREM2 and C1q both regulate hippocampal synapse formation. |
