Cheung A

References (3)

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