一般口演（Oral）

Oral Synapse Formation, Maturation, Maintenance 一般口演シナプス形成・成熟・維持

7月26日（金）8:30～8:45　第9会場（朱鷺メッセ　3F　306+307） 2O-09m1-1 IIa型受容体ホスファターゼとシナプスオーガナイザーとのシナプスを跨ぐ複合体の構造基盤 Atsushi Yamagata（山形敦史）¹，Sakurako Goto-Ito（後藤（伊藤）桜子）¹，Yusuke Sato（佐藤裕介）¹，Tomoko Shiroshima（城島知子）¹，Asami Maeda（前田亜沙美）¹，Tomoyuki Yoshida（吉田知之）^2,5，Takeshi Uemura（植村健）^3,4，Shuya Fukai（深井周也）^1,4 ¹東京大学・定量生命科学研究所 ²富山大学医学部・分子神経科学講座 ³信州大学医学部・基盤研究支援センター・遺伝子実験支援部門 ⁴JST CREST ⁵JSTさきがけ Synaptic organizers are cell-adhesion molecules that can induce synaptic differentiation in neurons. Selective pairs of pre- and postsynaptic organizers form heterogeneous complexes across the synaptic cleft. The type IIa receptor protein tyrosine phosphatase (IIa RPTP) family is a major class of presynaptic organizers. To date, six different synaptic organizers (IL1RAPL1, IL-1RAcP, Slitrks, SALMs, TrkC and NGL-3) have been identified as the postsynaptic partners of IIa RPTPs. Many of their selective pairings are controlled by splicing-derived short peptide insertions called "mini-exon peptides" in IIa RPTPs. We have investigated the mechanisms of the splicing-dependent interactions between PTPδ (one of the three IIa RPTPs in mammals) and IL1RAPL1, IL-1RAcP, or Slitrk2, using X-ray crystallography and structure-based mutational analyses at the molecular and cellular levels. Two mini-exon peptides (meA and meB) are contained in the N-terminal three immunoglobulin-like (Ig) domains of IIa RPTPs: meA is located within the second Ig domain, whereas meB is between the second and third Ig domains. The structures of PTPδ in complex with IL1RAPL1, IL-1RAcP, or Slitrk2 revealed that these two mini-exon peptides function as either a binding-epitope or an adjustable linker that enables the second and third Ig domains of PTPδ to simultaneously interact with specific domains of postsynaptic partners. In addition, we solved the crystal structure of PTPδ in complex with SALM5. The structure reveals that SALM5:PTPδ forms a 2:2 complex. Homo-dimerization of SALM5 is essential for synaptogenic activity. We describe our recent advances of the structural analyses of PTPδ and its postsynaptic organizer partners.		7月26日（金）8:45～9:00　第9会場（朱鷺メッセ　3F　306+307） 2O-09m1-2 成熟後の小脳における登上線維の形成・除去を担うC1ql1-Bai3シグナリングのダイナミックな役割 Takahiro Aimi（会見昂大），Wataru Kakegawa（掛川渉），Michisuke Yuzaki（柚﨑通介）慶應大医生理 Activity-dependent synapse formation and elimination are thought to serve as fundamental processes underlying learning and memory. Cerebellar Purkinje cells (PCs) have served as a good model system to study the mechanisms underlying developmental synapse elimination. While multiple climbing fibers (CFs) innervate immature PCs, they are eventually eliminated during neonatal period, leaving a single "winner" CF input. We previously found that C1ql1, a C1q-family protein secreted from CFs, bound to brain-specific angiogenesis inhibitor 3 (BAI3), an adhesion G protein-coupled receptor expressed in PCs, not only facilitate elimination of loser CFs, but also strengthen a winner CF during development (Kakegawa et al., Neuron, 2015). Although C1ql1 and Bai3 remain highly expressed in adult cerebellum, it remains unclear whether and how they function in mature CF synapses . Here, we show that appropriate levels of Bai3 are essential to maintain 1:1 innervation pattern at CF-PC synapses throughout life by overexpressing or knocking down Bai3 in adult PCs. Winner CF synapses were weakened by knockdown of Bai3 in adult PCs. Conversely, PCs become re-innervated by multiple CFs by overexpression of Bai3 in adult PCs, indicating that CFs possess synaptogenic capacity throughout life. Since family proteins closely related to C1ql1 and Bai3 are expressed in various brain regions, similar mechanisms likely mediate certain aspects of activity-dependent synaptic changes.

7月26日（金）9:00～9:15　第9会場（朱鷺メッセ　3F　306+307） 2O-09m1-3 アミロイドβシナプス障害におけるNeurexinの関与 Hideto Takahashi（高橋秀人）^1,2,3 ¹モントリオール臨床医学研究所, モントリオール, カナダ ²モントリオール大学・医、モントリオール、カナダ ³マギル大学・医、モントリオール、カナダ Synapse dysfunction and loss are hallmarks of early stage Alzheimer's disease (AD) and correlate with cognitive impairment. As an early pathological feature of AD, amyloid-beta (Aβ) is over-produced and forms soluble oligomers (AβOs) that impair synaptic transmission and promote synapse loss. Yet the molecular mechanisms underlying AβO-induced synapse pathology remain unclear. Normal synapse formation and maintenance depend on trans-synaptic adhesion and organization complexes. Here, we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays using non-neuronal cells co-cultured with rat hippocampal neurons, AβOs specifically diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and LRRTM2, but not that induced by type IIa receptor-type protein tyrosine phosphatase interactors including TrkC and Slitrk2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging using pH-sensitive green fluorescent protein-tagged NRX1β revealed that AβO treatment significantly reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. Moreover, in transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing the surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology in AD.		7月26日（金）9:15～9:30　第9会場（朱鷺メッセ　3F　306+307） 2O-09m1-4 神経活動とセプチンに依存した樹状突起棘への小胞体侵入による記憶の長期化 Makoto Kinoshita（木下専）¹，Natsumi Ageta-Ishihara（上田-石原奈津実）¹，Yugo Fukazawa（深澤有吾）²，Tsuyoshi Miyakawa（宮川剛）³，Keizo Takao（高雄啓三）⁴，Haruhiko Bito（尾藤晴彦）⁵ ¹名古屋大院理生命理学 ²福井大医組織細胞形態・神経科学 ³藤田医大総医研システム医科学 ⁴富山大院生命融合科学教育 ⁵東京大院医神経生化学 Memory for spatial contextual information depends mainly on neural circuits connecting the entorhinal cortex (EC) and hippocampus. Dentate gyrus (DG) granule cells (DGCs) are unique in their low firing rate in response to glutamatergic inputs from EC via the perforant path (pp), due to GABAergic tonic inhibition. The high-threshold property of the pp-DG synapse is thought to implement sparse coding for the differentiation among similar inputs by filtering information flow into the hippocampus. However, molecular basis of these and other unique properties of the pp-DG synapse remains unclear. Here we show that SEPT3, a subunit of the septin cytoskeleton, abounds in DGCs and pp-DG synapses. Sept3-null (KO) mice perform normally in an unbiased systematic behavioral screening, including spatial orientation and working memory (radial maze test), and anxiety-associated long-term spatial memory (Barnes maze test). Intriguingly, however, KO mice appear to differentiate cubic and cylindrical places upon reexposure after 2 h, but not after 24 h (non-associative place recognition test). These data indicate that SEPT3 plays a positive role for the retention of non-associative memory for spatial contexts, or a negative role for the generalization. To narrow down brain regions and neuronal populations responsible for the defect, and to exclude possible developmental anomalies, we conduct local, subacute depletion of SEPT3 from bilateral DG of wildtype mice, and local supplementation of SEPT3 into bilateral DG of KO mice, which respectively recapitulates and rescues the defect. The pp-DG synapses in KO mice are normal in electrophysiological and ultrastructural properties, except for a significant scarcity of smooth endoplasmic reticulum (sER), a Ca²⁺ reservoir, in dendritic spines. The sER anomaly is recapitulated in vitro by SEPT3 depletion (but not by the depletion of core subunit SEPT7) from primary cultured rat DGCs (but not CA pyramidal neurons). The DGC-selective requirement of SEPT3 points to 1) a molecular basis for the unique properties of DGCs, 2) a SEPT3-specific function which is not shared by other septin subunits, and 3) a novel gating mechanism that regulates the entry of sER from dendritic shaft into spines.