Craig, AM and Kang, Y. Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol 17: 43-52

Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver V6T 2B5, Canada.
Current Opinion in Neurobiology (Impact Factor: 6.63). 03/2007; 17(1):43-52. DOI: 10.1016/j.conb.2007.01.011
Source: PubMed


Neurexins and neuroligins are emerging as central organizing molecules for excitatory glutamatergic and inhibitory GABAergic synapses in mammalian brain. They function as cell adhesion molecules, bridging the synaptic cleft. Remarkably, each partner can trigger formation of a hemisynapse: neuroligins trigger presynaptic differentiation and neurexins trigger postsynaptic differentiation. Recent protein interaction assays and cell culture studies indicate a selectivity of function conferred by alternative splicing in both partners. An insert at site 4 of beta-neurexins selectively promotes GABAergic synaptic function, whereas an insert at site B of neuroligin 1 selectively promotes glutamatergic synaptic function. Initial knockdown and knockout studies indicate that neurexins and neuroligins have an essential role in synaptic transmission, particularly at GABAergic synapses, but further studies are needed to assess the in vivo functions of these complex protein families.

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    • "Moreover, we show that Nlgn2 deletion in the BA leads to a specific loss of perisomatic inhibitory postsynaptic components, but leaves perisomatic inhibitory presynaptic innervation and overall number of inhibitory pre-or postsynapses in the neuropil unaffected, which is in agreement with previous studies on the hippocampus of Nlgn2 KO mice (Jedlicka et al., 2011; Poulopoulos et al., 2009). This finding is particularly interesting in light of our observation that almost all gephyrin-positive structures in BA contain Nlgn2, indicating that the loss of Nlgn2 at non-perisomatic synapses is compensated by other synaptic adhesion molecules such as b-dystroglycan (Craig and Kang, 2007; Panzanelli et al., 2011). Our data are also consistent with the observation that Nlgn2 deletion in the cerebral cortex specifically affects synaptic connections made by axons of PV- Fig. 6 "
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    ABSTRACT: Neuroligin 2 (Nlgn2) is a synaptic adhesion protein that plays a central role in the maturation and function of inhibitory synapses. Nlgn2 mutations have been associated with psychiatric disorders such as schizophrenia, and in mice, deletion of Nlgn2 results in a pronounced anxiety phenotype. To date, however, the molecular and cellular mechanisms linking Nlgn2 deletion to psychiatric phenotypes remain completely unknown. The aim of this study was therefore to define the role of Nlgn2 in anxiety-related neural circuits. To this end, we used a combination of behavioral, immunohistochemical, and electrophysiological approaches in Nlgn2 knockout (KO) mice to expand the behavioral characterization of these mice and to assess the functional consequences of Nlgn2 deletion in the amygdala. Moreover, we investigated the differential activation of anxiety-related circuits in Nlgn2 KO mice using a cFOS activation assay following exposure to an anxiogenic stimulus. We found that Nlgn2 is present at the majority of inhibitory synapses in the basal amygdala, where its deletion affects postsynaptic structures specifically at perisomatic sites and leads to impaired inhibitory synaptic transmission. Following exposure to an anxiogenic environment, Nlgn2 KO mice show a robust anxiety phenotype as well as exacerbated induction of cFOS expression specifically in CaMKII-positive projection neurons, but not in parvalbumin- or somatostatin-positive interneurons. Our data indicate that Nlgn2 deletion predominantly affects inhibitory synapses onto projection neurons in basal amygdala, resulting in decreased inhibitory drive onto these neurons and leading to their excessive activation under anxiogenic conditions. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 06/2015; DOI:10.1016/j.neuropharm.2015.06.016 · 5.11 Impact Factor
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    • "Neuronal cell adhesion molecules (nCAMs) are involved in regulating synapse function, synaptic properties and neurotransmission (Dalva et al., 2007; Sandi, 2004; Südhof, 2008). Neuroligins (nlgns) are postsynaptic type-I membrane proteins linking pre-and postsynaptic membranes by binding to presynaptic neurexins (nrxns) (Chih et al., 2005; Craig and Kang, 2007; Südhof, 2008). The nlgn family members are encoded by 4 genes in mammals, nlgn1-4, and appear in different postsynaptic specializations (Südhof, 2008). "
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    ABSTRACT: Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 02/2015; 55:128-143. DOI:10.1016/j.psyneuen.2015.02.016 · 4.94 Impact Factor
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    • "Cell–cell adhesion plays an integral role in synapse formation and development, synaptogenesis and synaptic plasticity (Bukalo and Dityatev, 2012; Dalva et al., 2007; Li and Sheng, 2003; Washbourne et al., 2004; Yamagata et al., 2003). The most extensively described cell adhesion molecules in synaptic transmission and formation are neurexins, neuroligins, cadherins and members of the immunoglobulin (Ig) superfamily (Craig and Kang, 2007; Dean and Dresbach, 2006; Lisé and El-Husseini, 2006; Scott and Palmer, 1993; Shapiro et al., 2007; Takeichi, 2007). Unlike the classical cell–cell adhesion molecules, the adhesion GPCRs are not characterised by their roles in regulation and/or development of the nervous system. "
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    ABSTRACT: The origin and evolution of the nervous system is one of the most intriguing and enigmatic events in biology. The recent sequencing of complete genomes from early metazoan organisms provides a new platform to study the origins of neuronal gene families. This review explores the early metazoan expansion of the largest integral transmembrane protein family, the G protein-coupled receptors (GPCRs), which serve as molecular targets for a large subset of neurotransmitters and neuropeptides in higher animals. GPCR repertories from four pre-bilaterian metazoan genomes were compared. This includes the cnidarian Nematostella vectensis and the ctenophore Mnemiopsis leidyi, which have primitive nervous systems (nerve nets), the demosponge Amphimedon queenslandica and the placozoan Trichoplax adhaerens, which lack nerve and muscle cells. Comparative genomics demonstrate that the rhodopsin and glutamate receptor families, known to be involved in neurotransmission in higher animals are also widely found in pre-bilaterian metazoans and possess substantial expansions of rhodopsin-family-like GPCRs. Furthermore, the emerging knowledge on the functions of adhesion GPCRs in the vertebrate nervous system provides a platform to examine possible analogous roles of their closest homologues in pre-bilaterians. Intriguingly, the presence of molecular components required for GPCR-mediated neurotransmission in pre-bilaterians reveals that they exist in both primitive nervous systems and nerve-cell-free environments, providing essential comparative models to better understand the origins of the nervous system and neurotransmission. © 2015. Published by The Company of Biologists Ltd.
    Journal of Experimental Biology 02/2015; 218(4):562-571. DOI:10.1242/jeb.110312 · 2.90 Impact Factor
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