■Kainate receptors have a non-channel, non-metabolizing effect.、Controls climbing fiber synapse formation and plasticity in the cerebellum (Cell Rep) 2024.6.30 Kakegawa W*, Paternain AV, Matsuda K, Isabel AM, Iida I, Miura E, Nozawa K, Yamasaki T, Sakimura K, Yuzaki M **, Lerma J*. Kainate receptors regulate synaptic integrity and plasticity by forming a complex with synaptic organizers in the cerebellum. Cell Reports 43:114427, 2024.
Kainate-type glutamate receptors (KARs)、through ionotropic and metabotropic effects.、Involved in various neuropsychiatric and neurological disorders。However、Compared to AMPA-type and NMDA-type glutamate receptors,、The biological properties of KARs remain unclear in many ways。In this research、K.A.R.、Apart from ion channels and metabotropic effects、We revealed that climbing fibers (CFs) and Purkinje cells (PCs) in the cerebellum play an important role in synapse formation and synaptic plasticity.。The amino-terminal domain (ATD) of the KAR subunit GluK4 is、Binds to C1ql1 secreted by CF、Furthermore, we discovered that it associates with Bai3, an adhesive G protein-coupled receptor expressed on PC dendrites.。In mice lacking GluK4,、The number of CF-PC synapses decreases together with C1ql1 and Bai3 at synapses.、Synaptic plasticity and cerebellum-dependent oculomotor learning are impaired。surprisingly、When the ATD of GluK4 (which has no intracellular domain or channel domain) is expressed in PCs,、The phenotype of GluK4 KO mice was restored。These findings are、We show that KAR acts as a synaptic scaffold by forming the KAR-C1ql1-Bai3 complex。In joint research with the Juan Lerma laboratory in Spain.、Associate Professor Kakegawa and Ana Paternain are first authors。

■There is no evidence that GluD receptors act as ligand-gated ion channels. (This paper has been published in PNAS) 2024.6.30 Itoh M, Piot L, Mony L, Paoletti P*, Yuzaki M.* Lack of evidence for direct ligand-gated ion channel activity of GluD receptors Proc Natl Acad Sci USA 121:e2406655121, 2024.
Delta receptors (GluD1 and GluD2)、A member of the ionotropic glutamate receptor family、plays a central role in many neurodevelopmental and psychiatric disorders。GluD is、Not related to ion channel activity、By forming a tripartite complex across synapses with the secreted synaptogenic molecules Cbln and neurexin (Nrxn).、Controls synapse formation and maturation。On the other hand、in recent years、Only when GluD2 forms the Nrxn/Cbln/GluD2 complex、It was reported that it functions as an ion channel that responds to D-serine and glycine.。Nozawa-kun, together with Hayashi-san、We、Currents induced by D-serine and glycine in ectopic cells and neurons、Proved that GluD is not directly involved as an ion channel。This finding is、It makes an important contribution to the ongoing discussion on the function of GluD.。In collaboration with Pierre Paoletti laboratory、Mr. Ito and Laura Piot acted as first authors.。

■ Extrasynaptic expression of α3β4-containing nicotinic acetylcholine receptors in the medial habenula-interpeduncular nucleus pathway of mice (Sci Rep) 2024.6.20 Tsuzuki A, Yamasaki M, Konno K, Miyazaki T, Takei N, Tomita S, Yuzaki M, Watanabe M.Abundant extrasynaptic expression of α3β4-containing nicotinic acetylcholine receptors in the medial habenula–interpeduncular nucleus pathway in mice. Scientific Reports 14:14193, 2024..
Nicotinic acetylcholine receptors (nAChRs) in the medial habenula-interpeduncular pathway、plays an important role in nicotine-related behavior。In this pathway, nAChR α3 and β4 subunits are highly expressed.。Until now, the expression pattern of α3β4-containing nAChRs was、Because specific antibodies were not available、almost unknown。Nozawa-kun, together with Hayashi-san、Novel specific antibodies and、Using glyoxal fixation method、α3β4-containing nAChRs in this pathway are mainly found in extrasynaptic regions.)revealed that there is。This research is part of a special promotion research project.、This work was led by Professor Yamazaki of the Watanabe Laboratory at Hokkaido University.。

■LGI1 is、Secreted from axons in response to neural activity and suppresses glutamate release (Cell Reports) 2024.5.28 Cuhadar U, Footwear-Reyes L, Pascual-Caro C, Aberra AS, Ritzau-Jost A, Aggarwal A, Ibata K, Podgorski K, Yuzaki M, Geiss C, Hallerman S, Jump MB, by Juan-Sanz J. Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission. Cell Rep. 43:114186, 2024..
LGI1 is a synaptogenic molecule belonging to extracellular scaffold proteins。LGI1 is secreted in response to neural activity and promotes synapse formation.、Found to suppress glutamate release。Interestingly, Cbln1 is tetanus toxin (TeNT)(VAMP1-3 independent)、We previously reported that it is secreted by Syntaxin-4 and SNAP49-dependent SNAREs.。In contrast, LGI1 secretion was partially inhibited by TeNT.、Because it does not depend on SNAP29、found to be released by separate SNARE complexes。In this paper, Yuzaki Lab conducted joint research on analysis technology for SNARE complexes.。

■CPTX is、Promoting synapse formation on iPS transplanted cells in spinal cord injury model mice (Stem Cell Reports) 2024.2.3 Saijo Y, Nagoshi N, Kawai M, Kitagawa T, Suematsu Y, Ozaki M, Shinozaki M, Kohyama J, Shibata S, Takeuchi K, Nakamura M, Yuzaki M, Okano H. Human-induced pluripotent stem cell-derived neural stem/progenitor cell ex vivo gene therapy with synaptic organizer CPTX for spinal cord injury. Stem Cell Reports S2213-6711(24)00010-9, 2024..
Transplantation of neural stem/progenitor cells (NS/PC) derived from human induced pluripotent stem cells (hiPSC)、Shows promise in animal models of spinal cord injury (SCI)。For recovery of motor function、It is important to establish functional synaptic connections between transplanted neurons and host neurons。In this paper,、We have developed ex vivo gene therapy in which the artificial synaptic connector CPTX developed by Yuzaki Lab is expressed in hiPSC-NS/PCs in advance and then transplanted.。Using immunodeficient transgenic SCI model rats、Where histological and functional analysis was performed、It was revealed that the formation of excitatory synapses at the transplantation site of CPTX-expressing hiPSC-NS/PCs was significantly increased.。Also、Tracking of retrograde monosynapses、CPTX has been shown to cause extensive integration of transplanted neurons into surrounding neural tracts.、Motor function and spinal conduction also improved.。This study、Orthopedic surgeon Saijo-san、This is a joint research with Okano Lab.。

■DSCAM is、Controls the perisynaptic localization of GLAST in Bergmann glia and participates in synapse formation（Nature Commun）2024.2.3 Dewa KI, Arimu N, Kakegawa W, Itoh M, Adachi T, Miyashita S, Inoue YU, Hizawa K, Hori K, Honjoya N, Yagishita H, Taya S, Miyazaki T, Usui C, Tatsumoto S, Tsuzuki A, Uetake H, Sakai K, Yamakawa K, Sasaki T, Nagai J, Kawaguchi Y, Sone M, Inoue T, Go Y, Ichinohe N, Kaibuchi K, Watanabe M, Koizumi S, Yuzaki M, Hoshino M. Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation. Nat Commun. 15:458, 2024..

in the central nervous system、Astrocytes clear glutamate from the synaptic cleft.、Achieves proper synaptic function。However、How does the astrocytic glutamate transporter GLAST function around synapses?、it was still unclear。In this paper、Cell adhesion molecule (DSCAM) expressed in Purkinje cells、By controlling the localization of GLAST expressed in Bergmann glia、Climbing fibers were shown to be involved in Purkinje cell synapse formation and cerebellar motor learning.。This is a huge amount of work done by Mr. Dewa of Hoshino Lab.。For the Yuzaki lab, Kakegawa was in charge of electrophysiological analysis and eye movement learning test.。

■Bioorthogonal chemical labeling of endogenous neurotransmitter receptors in the living mouse brain（PNAS）2024.1.31 Nonaka H, Sakamoto S, Shiraiwa K, Ishikawa M, Tamura T, Okuno K, Kondo T, Kiyonaka S, Susaki EA, Shimizu C, Ueda HR, Kakegawa W, Arai I, Yuzaki M, Hamachi I. Bioorthogonal chemical labeling of endogenous neurotransmitter receptors in living mouse brains. Proc Natl Acad Sci USA. 121:e2313887121, 2024..

How to covalently chemically label proteins without genetic manipulation、is a powerful method for analyzing receptors。However、Selective target receptor labeling in the brain has not yet been established。In this research led by Mr. Nonaka of Kyoto University's Hamachi Laboratory,、using ligand-directed chemical reactions、We show that synthetic probes can selectively bind to target endogenous receptors in the brain of living mice.。Kakegawa of Yuzaki Lab、As part of the joint research between CREST and ERATO, Arai、In this study, we showed that chemical labeling does not change receptor function.。

■Another hidden face of GluD1 in inhibitory synapses（Cell Research）2024.1.24 Masayuki Itoh, Michisuke Yuzaki. The hidden face of GluD1 at inhibitory synapses. Cell Res. 2024 Jan 23.

The δ-type glutamate receptors (GluD1 and GluD2) belong to the ionotropic glutamate receptors.、It has long been called an orphan receptor because it does not bind glutamate.。GluD2 isexcitatory synapseIn、① Binds to Cbln1 released from the presynapse to control synapse formation and maintenance、② Binds to D-Ser released by glia and induces synaptic plasticity LTD、It was found that the function of。Interestingly、GluD1 isinhibitory synapseIn、① Binds with Cbln4 released from the presynapse to control synapse formation and maintenance。However, it was unclear whether GluD1 controls synaptic plasticity.。Nozawa-kun, together with Hayashi-san、By Piot et al.、GluD1 is、②Showed to bind to GABA and control LTP at inhibitory synapses。In this review、We introduce this paper and summarize the remaining issues.。