Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction

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

Analyzing powers Ayy, Axx, Axz and Ay in the dd->3Hen reaction at 270 MeV

The data on the tensor Ayy, Axx, Axz and vector Ay analyzing powers in the dd->3Hen obtained at Td= 270 MeV in the angular range 0 - 110 degrees in the c.m. are presented. The observed negative sign of the tensor analyzing powers Ayy, Axx and Axz at small angles clearly demonstrate the sensitivity to the ratio of the D and S wave component of the 3He wave function. However, the one-nucleon exchange calculations by using the standard 3He wave functions have failed to reproduce the strong variation of the tensor analyzing powers as a function of the angle in the c.m.Comment: 8 pages, 7 figures, 4 tables. Submitted to EPJ

Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus

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

The Endocannabinoid 2-Arachidonoylglycerol Produced by Diacylglycerol Lipase α Mediates Retrograde Suppression of Synaptic Transmission

SummaryEndocannabinoids 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 α (DGLα) and β (DGLβ). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLα knockout mice, whereas the retrograde suppression was intact in DGLβ knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLα knockout brains, whereas the 2-AG content was normal in DGLβ 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 DGLα, but not by DGLβ, mediates retrograde suppression at central synapses

A Specific Neuroligin3-αNeurexin1 Code Regulates GABAergic Synaptic Function in Mouse Hippocampus [preprint]

Synapse formation and regulation require 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 αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn interactions generate distinct functional properties at synapses

Determination of the Gamow-Teller Quenching Factor from Charge Exchange Reactions on 90Zr

Double differential cross sections between 0-12 degrees were measured for the 90Zr(n,p) reaction at 293 MeV over a wide excitation energy range of 0-70 MeV. A multipole decomposition technique was applied to the present data as well as the previously obtained 90Zr(p,n) data to extract the Gamow-Teller (GT) component from the continuum. The GT quenching factor Q was derived by using the obtained total GT strengths. The result is Q=0.88+/-0.06 not including an overall normalization uncertainty in the GT unit cross section of 16%.Comment: 11 papes, 4 figures, submitted to Physics Letters B (accepted), gzipped tar file, changed content

認知症高齢者の日常生活ケアにかかわる意思決定能力の特徴とその関連要因の検討

本研究の目的は,認知症高齢者の意思決定能力を捉える試みとして,日常生活ケアに関する設問への回答から,意思決定に必要な4つの機能的能力(「理解」「認識」「選択の表明」「論理的思考」)の特徴と関連要因を検討することである.特別養護老人ホームに居住する認知症高齢者24人を対象に,各能力を評価するための面接調査を2回実施し,回答の有無と一貫性および関連要因を分析した.結果,情報を「理解」する能力は認知機能障害の重症化に応じて減少する傾向を示したが,他の能力には認知機能との単純な関連を認めなかった.生活状況を「認識」する能力は,認知機能と日常生活動作能力の低下に応じて,対象者の一貫した認識と介護職員の評価がずれる傾向を示した.「選択の表明」能力では,選択の一貫性と認知機能との関連が設問の内容に左右される可能性を示した.「論理的思考」能力も設問内容の影響を受ける傾向にあったが,統計学的に関連を示す要因はなかった.The purpose of this research was to clarify features of four functional abilities necessary for decision-making and inquest related factors based on responses to the questionnaire about daily care for living. In order to assess each feature of abilities, 24 elders with dementia who were living in nursing homes were interviewed two times, and differences and consistency between responses on first interview and second were checked. It was found that ability to understand information declined as cognitive function became severe; however, simple relationship was not found between other abilities and change of cognitive function. As cognitive function and ability of daily living got worse, difference of assessment about ability to appreciate living situation became bigger between subjects and care workers. About ability to express a choice, relationship between consistency on selection and cognitive function was found to be affected by contents of questionnaire. It was also found that ability of reasoning was tend to be affected by contents of questionnaire,however; statistical significance was not found on their relationship

Specific Neuroligin3-alphaNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus

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

Measurement of the tensor analyzing power T20 in the dd->^3Hen and dd->^3Hp at intermediate energies and at zero degree

The data on the tensor analyzing power T20 in the dd->^3Hen and dd-> ^3Hp reactions at 140, 200 and 270 MeV of the deuteron kinetic energy and at zero degree obtained at RIKEN Accelerator Research Facility are presented. The observed positive sign of T20 clearly demonstrates the sensitivity to the D/S wave ratios in the ^3He and ^3H in the energy domain of the measurements. The T20 data for the ^3He-n and ^3H-p channels are in agreement within experimental accuracy.Comment: 9 pages, 3 figures, submitted in Phys.Lett.

Chronic Alterations in Monoaminergic Cells in the Locus Coeruleus in Orexin Neuron-Ablated Narcoleptic Mice

Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC) and dorsal raphe (DR) nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT) neurons and noradrenergic (NA) neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy. © 2013 Tsujino et al