Uchigashima M

References (9)

Title : Regulation of Presynaptic Release Machinery by Cell Adhesion Molecules - Uchigashima_2023_Adv.Neurobiol_33_333
Author(s) : Uchigashima M , Hayashi Y , Futai K
Ref : Adv Neurobiol , 33 :333 , 2023
Abstract : The synapse is a highly specialized asymmetric structure that transmits and stores information in the brain. The size of pre- and postsynaptic structures and function is well coordinated at the individual synapse level. For example, large postsynaptic dendritic spines have a larger postsynaptic density with higher alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) number on their surface, while juxtaposing presynaptic terminals have a larger active zone and higher release probability. This indicates that pre- and postsynaptic domains bidirectionally communicate to coordinate assembly of specific molecules on both sides of the synaptic cleft. Cell adhesion molecules (CAMs) that localize at synapses form transsynaptic protein interactions across the synaptic cleft and play important roles in synapse formation and regulation. The extracellular domain of CAMs is essential for specific synapse formation and function. In contrast, the intracellular domain is necessary for binding with synaptic molecules and signal transduction. Therefore, CAMs play an essential role on synapse function and structure. In fact, ample evidence indicates that transsynaptic CAMs instruct and modulate functions at presynaptic sites. This chapter focuses on transsynaptic protein interactions that regulate presynaptic functions emphasizing the role of neuronal CAMs and the intracellular mechanism of their regulation.
ESTHER : Uchigashima_2023_Adv.Neurobiol_33_333
PubMedSearch : Uchigashima_2023_Adv.Neurobiol_33_333
PubMedID: 37615873

Title : Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction - Uchigashima_2021_Front.Mol.Neurosci_14_749164
Author(s) : Uchigashima M , Cheung A , Futai K
Ref : Front Mol Neurosci , 14 :749164 , 2021
Abstract : Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.
ESTHER : Uchigashima_2021_Front.Mol.Neurosci_14_749164
PubMedSearch : Uchigashima_2021_Front.Mol.Neurosci_14_749164
PubMedID: 34690695

Title : Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus - Uchigashima_2020_J.Biol.Chem__
Author(s) : Uchigashima M , Leung M , Watanabe T , Cheung A , Le T , Pallat S , Dinis ALM , Watanabe M , Imamura Kawasawa Y , Futai K
Ref : Journal of Biological Chemistry , : , 2020
Abstract : Synapse formation is a dynamic process essential for the development and maturation of the neuronal circuitry in the brain. At the synaptic cleft, transsynaptic protein-protein interactions are major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity, and dysregulation of the E-I balance has been implicated in neurodevelopmental disorders, including autism spectrum disorders. However, the molecular mechanisms underlying the E-I balance remain to be elucidated. Here, using single-cell transcriptomics, immunohistochemistry and electrophysiology approaches to murine CA1 pyramidal neurons obtained from organotypic hippocampal slice cultures, we investigate Neuroligin (Nlgn) genes that encode a family of postsynaptic adhesion molecules known to shape excitatory and inhibitory synaptic function. We demonstrate that the NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform-dependent manner at hippocampal CA1 synapses. We also found that distinct subcellular localizations of the NLGN3 isoforms contribute to the functional differences observed among these isoforms. Finally, results from single-cell RNA-Seq analyses revealed that Nlgn1 and Nlgn3 are the major murine Nlgn genes and that the expression levels of the Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons. Our results delineate isoform-specific effects of Nlgn genes on the E-I balance in the murine hippocampus.
ESTHER : Uchigashima_2020_J.Biol.Chem__
PubMedSearch : Uchigashima_2020_J.Biol.Chem__
PubMedID: 32381505

Title : Specific Neuroligin3-alphaNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus - Uchigashima_2020_Elife_9_
Author(s) : Uchigashima M , Konno K , Demchak E , Cheung A , Watanabe T , Keener DG , Abe M , Le T , Sakimura K , Sasaoka T , Uemura T , Imamura Kawasawa Y , Watanabe M , Futai K
Ref : Elife , 9 : , 2020
Abstract : Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the alphaNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic alphaNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn signaling generates distinct functional properties at synapses.
ESTHER : Uchigashima_2020_Elife_9_
PubMedSearch : Uchigashima_2020_Elife_9_
PubMedID: 33355091

Title : Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures - Uchigashima_2016_Proc.Natl.Acad.Sci.U.S.A_113_4206
Author(s) : Uchigashima M , Ohtsuka T , Kobayashi K , Watanabe M
Ref : Proc Natl Acad Sci U S A , 113 :4206 , 2016
Abstract : Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor alpha1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.
ESTHER : Uchigashima_2016_Proc.Natl.Acad.Sci.U.S.A_113_4206
PubMedSearch : Uchigashima_2016_Proc.Natl.Acad.Sci.U.S.A_113_4206
PubMedID: 27035941

Title : Lack of molecular-anatomical evidence for GABAergic influence on axon initial segment of cerebellar Purkinje cells by the pinceau formation - Iwakura_2012_J.Neurosci_32_9438
Author(s) : Iwakura A , Uchigashima M , Miyazaki T , Yamasaki M , Watanabe M
Ref : Journal of Neuroscience , 32 :9438 , 2012
Abstract : The axon initial segment (AIS) of cerebellar Purkinje cells (PCs) is embraced by ramified axons of GABAergic basket cells (BCs) called the pinceau formation. This unique structure has been assumed to be a device for the modulation of PC outputs through electrical and/or GABAergic inhibition. Electrical inhibition is supported by enriched potassium channels, absence of sodium channels, and developed septate-like junctions between BC axons. The neurochemical basis for GABAergic inhibition, however, has not been well investigated. Here we addressed this issue using C56BL/6 mice. First, we confirmed previous observations that typical synaptic contacts were rare and confined to proximal axonal portions, with the remaining portions being mostly covered by astrocytic processes. Then we examined the expression of molecules involved in GABAergic signaling, including GABA synthetic enzyme glutamic acid decarboxylase (GAD), vesicular GABA transporter vesicular inhibitory amino acid transporter (VIAAT), cytomatrix active zone protein bassoon, GABA receptor GABA(A)Ralpha1, and cell adhesion molecule neuroligin-2. These molecules were recruited to form a functional assembly at perisomatic BC-PC synapses and along the AIS of hippocampal and neocortical pyramidal cells. GAD and VIAAT immunogold labeling was five times lower in the pinceau formation compared with perisomatic BC terminals and showed no accumulation toward the AIS. Moreover, bassoon, neuroligin-2, and GABA(A)Ralpha1 formed no detectable clusters along the ankyrin-G-positive AIS proper. These findings indicate that GABAergic signaling machinery is organized loosely and even incompletely in the pinceau formation. Together, BCs do not appear to exert GABAergic synaptic inhibition on the AIS, although the mode of action of the pinceau formation remains to be explored.
ESTHER : Iwakura_2012_J.Neurosci_32_9438
PubMedSearch : Iwakura_2012_J.Neurosci_32_9438
PubMedID: 22764252

Title : Localization of acetylcholine-related molecules in the retina: implication of the communication from photoreceptor to retinal pigment epithelium - Matsumoto_2012_PLoS.One_7_e42841
Author(s) : Matsumoto H , Shibasaki K , Uchigashima M , Koizumi A , Kurachi M , Moriwaki Y , Misawa H , Kawashima K , Watanabe M , Kishi S , Ishizaki Y
Ref : PLoS ONE , 7 :e42841 , 2012
Abstract : It has been long speculated that specific signals are transmitted from photoreceptors to the retinal pigment epithelium (RPE). However, such signals have not been identified. In this study, we examined the retinal expression and localization of acetylcholine-related molecules as putative candidates for these signals. Previous reports revealed that alpha7 nicotinic acetylcholine receptors (nAChRs) are present in the microvilli of RPE cells that envelope the tips of photoreceptor outer segments (OS). Secreted mammalian leukocyte antigen 6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1) is a positive allosteric modulator of the alpha7 nAChR. Therefore, we first focused on the expression of SLURP-1. SLURP-1 mRNA was expressed in the outer nuclear layer, which is comprised of photoreceptor cell bodies. SLURP-1 immunoreactivity co-localized with rhodopsin and S-opsin in photoreceptor OS, while choline acetyltransferase (ChAT) and high affinity choline transporter (CHT-1) were also expressed in photoreceptor OS. Immunoelectron microscopy identified that the majority of SLURP-1 was localized to the plasma membranes of photoreceptor OS. These results provide evidence that SLURP-1 is synthesized in photoreceptor cell bodies and transported to photoreceptor OS, where SLURP-1 may also be secreted. Our findings suggest that photoreceptor OS communicate via neurotransmitters such as ACh and SLURP-1, while RPE cells might receive these signals through alpha7 nAChRs in their microvilli.
ESTHER : Matsumoto_2012_PLoS.One_7_e42841
PubMedSearch : Matsumoto_2012_PLoS.One_7_e42841
PubMedID: 22880119

Title : The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission - Tanimura_2010_Neuron_65_320
Author(s) : Tanimura A , Yamazaki M , Hashimotodani Y , Uchigashima M , Kawata S , Abe M , Kita Y , Hashimoto K , Shimizu T , Watanabe M , Sakimura K , Kano M
Ref : Neuron , 65 :320 , 2010
Abstract : Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase alpha (DGLalpha) and beta (DGLbeta). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLalpha knockout mice, whereas the retrograde suppression was intact in DGLbeta knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLalpha knockout brains, whereas the 2-AG content was normal in DGLbeta knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLalpha, but not by DGLbeta, mediates retrograde suppression at central synapses.
ESTHER : Tanimura_2010_Neuron_65_320
PubMedSearch : Tanimura_2010_Neuron_65_320
PubMedID: 20159446
Gene_locus related to this paper: human-DAGLA

Title : Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor - Yoshida_2006_J.Neurosci_26_4740
Author(s) : Yoshida T , Fukaya M , Uchigashima M , Miura E , Kamiya H , Kano M , Watanabe M
Ref : Journal of Neuroscience , 26 :4740 , 2006
Abstract : 2-arachidonoyl-glycerol (2-AG) is an endocannabinoid that is released from postsynaptic neurons, acts retrogradely on presynaptic cannabinoid receptor CB1, and induces short- and long-term suppression of transmitter release. To understand the mechanisms of the 2-AG-mediated retrograde modulation, we investigated subcellular localization of a major 2-AG biosynthetic enzyme, diacylglycerol lipase-alpha (DAGLalpha), by using immunofluorescence and immunoelectron microscopy in the mouse brain. In the cerebellum, DAGLalpha was predominantly expressed in Purkinje cells. DAGLalpha was detected on the dendritic surface and occasionally on the somatic surface, with a distal-to-proximal gradient from spiny branchlets toward somata. DAGLalpha was highly concentrated at the base of spine neck and also accumulated with much lower density on somatodendritic membrane around the spine neck. However, DAGLalpha was excluded from the main body of spine neck and head. In hippocampal pyramidal cells, DAGLalpha was also accumulated in spines. In contrast to the distribution in Purkinje cells, DAGLalpha was distributed in the spine head, neck, or both, whereas somatodendritic membrane was labeled very weakly. These results indicate that DAGLalpha is essentially targeted to postsynaptic spines in cerebellar and hippocampal neurons, but its fine distribution within and around spines is differently regulated between the two neurons. The preferential spine targeting should enable efficient 2-AG production on excitatory synaptic activity and its swift retrograde modulation onto nearby presynaptic terminals expressing CB1. Furthermore, different fine localization within and around spines suggests that the distance between postsynaptic 2-AG production site and presynaptic CB1 is differentially controlled depending on neuron types.
ESTHER : Yoshida_2006_J.Neurosci_26_4740
PubMedSearch : Yoshida_2006_J.Neurosci_26_4740
PubMedID: 16672646