Building Excitatory and Inhibitory Synapses: Balancing Neuroligin Partnerships

Levinson, Joshua N.; El‐Husseini, Alaa

doi:10.1016/j.neuron.2005.09.017

Cited by 146 publications

(102 citation statements)

References 29 publications

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“…Different affinities of the interactions between different neurexin-neuroligin pairs are combined with a selective linkage to components of glutamatergic versus GABAergic synapses, by mechanisms that are not yet understood. However, the significance of such a shared system is that alterations in stoichiometry of key players can be used to regulate the balance of excitatory and inhibitory inputs onto a neuron [40]. Recent in vivo studies indicate that neurexins and neuroligins have essential roles in synapse development -not in initial adhesion, but in recruitment of molecular components and maturation [47••].…”

Section: Discussionmentioning

confidence: 99%

Neurexin–neuroligin signaling in synapse development

Craig

Kang

2007

Current Opinion in Neurobiology

566

487

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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 β-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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Section: Discussionmentioning

confidence: 99%

Neurexin–neuroligin signaling in synapse development

Craig

Kang

2007

Current Opinion in Neurobiology

566

487

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“…The selective localization of NL1 and NL2 at excitatory and inhibitory synapses, respectively (11,13), has lead to the idea that these adhesion molecules may contribute to specify distinct types of synapse in an activity-dependent manner (15,16). Two potential mechanisms have been proposed to explain the synapse-specific localization of NLs: (1) intracellular interactions with scaffolding molecules or other postsynaptic proteins may recruit different NL isoforms to glutamatergic or GABAergic synapses (15); (2) synapse specificity may arise from selective extracellular interactions between distinct NL-neurexin isoform pairs (17,18).…”

Section: Synaptic Clustering Of Nl2 Is Independent Of Gaba a Receptormentioning

confidence: 99%

“…Importantly, NL1 is targeted to glutamatergic synapses (13,14), suggesting that different NLs may play an important role in specifying distinct types of synapse and in determining a balance between neuronal excitation and inhibition (15,16). The mechanisms responsible for the differential targeting of NL1 to glutamatergic synapses and NL2 to GABAergic synapses are unclear, although there is evidence that such specificity could arise either from intracellular interactions with postsynaptic scaffolds (15) or from selective extracellular binding of NL splice variants with neurexin isoforms (17,18). However, the binding partners of NL2 at GABA synapses are not known.…”

mentioning

confidence: 99%

Synapse formation and clustering of neuroligin-2 in the absence of GABA _A receptors

Patrizi

Scelfo

Viltono

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

114

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GABAergic synapses are crucial for brain function, but the mechanisms underlying inhibitory synaptogenesis are unclear. Here, we show that postnatal Purkinje cells (PCs) of GABAA␣1 knockout (KO) mice express transiently the ␣3 subunit, leading to the assembly of functional GABAA receptors and initial normal formation of inhibitory synapses, that are retained until adulthood. Subsequently, down-regulation of the ␣3 subunit causes a complete loss of GABAergic postsynaptic currents, resulting in a decreased rate of inhibitory synaptogenesis and formation of mismatched synapses between GABAergic axons and PC spines. Notably, the postsynaptic adhesion molecule neuroligin-2 (NL2) is correctly targeted to inhibitory synapses lacking GABAA receptors and the scaffold molecule gephyrin, but is absent from mismatched synapses, despite innervation by GABAergic axons. Our data indicate that GABAA receptors are dispensable for synapse formation and maintenance and for targeting NL2 to inhibitory synapses. However, GABAergic signaling appears to be crucial for activity-dependent regulation of synapse density during neuronal maturation.gephyrin ͉ Purkinje cell ͉ synaptogenesis T he identification of the factors that are critical for the assembly, maturation, and stabilization of synaptic connections remains a central puzzle in developmental neuroscience. Studies on cultured neurons have been invaluable for uncovering the molecular mechanisms of synaptogenesis (1, 2). Unfortunately, such studies can be influenced by varying experimental conditions, and their results often have not been replicated by in vivo analyses of gene knockout (KO) mice (3). As an alternative approach, gene deletion techniques allow investigating the in vivo function of genes that are believed to be critical for synapse formation (4-8). However, the premature death of newborn mutant mice has often prevented long-term analyses of synapse maturation and function. In the present study, we took advantage of a KO model that survives up to adulthood without a major phenotype, despite extensive loss of GABA-mediated function in specific populations of neurons.Specifically, we investigated the in vivo effects of a selective silencing of GABAergic transmission on the formation and longterm stability of GABAergic synapses, which provide the major inhibitory control over neuronal activity in the brain (9). By analogy to glutamatergic synapses, assembly of GABAergic synapses is believed to involve selective trans-synaptic interactions between adhesion molecules and cytosolic interactions with scaffolding proteins (2). Neuroligin-2 (NL2) is a postsynaptic adhesion molecule that localizes at GABAergic synapses and triggers synapse formation by interacting with presynaptic neurexins (10, 11). NL2 belongs to a family of related proteins also comprising NL1, NL3, and NL4 (12). Importantly, NL1 is targeted to glutamatergic synapses (13,14), suggesting that different NLs may play an important role in specifying distinct types of synapse and in determining a balance between n...

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“…This indicates that the balance of expression of distinct NLG-1 isoforms could underpin the generation of different postsynaptic identities. This study indicates how the dynamic splicing of a single gene in C. elegans nervous system might allow something of the synaptic diversity that the vertebrate neuroligins achieve through segregating function to distinct members of a multiple gene family (Chubykin et al, 2007;Levinson and El-Husseini, 2005;Mackowiak et al, 2014).…”

Section: Discussionmentioning

confidence: 89%

Analysis of splice variants for the C. elegans orthologue of human neuroligin reveals a developmentally regulated transcript

Calahorro

Holden‐Dye

O’Connor

2015

Gene Expression Patterns

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Building Excitatory and Inhibitory Synapses: Balancing Neuroligin Partnerships

Cited by 146 publications

References 29 publications

Neurexin–neuroligin signaling in synapse development

Neurexin–neuroligin signaling in synapse development

Synapse formation and clustering of neuroligin-2 in the absence of GABA _A receptors

Analysis of splice variants for the C. elegans orthologue of human neuroligin reveals a developmentally regulated transcript

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Building Excitatory and Inhibitory Synapses: Balancing Neuroligin Partnerships

Cited by 146 publications

References 29 publications

Neurexin–neuroligin signaling in synapse development

Neurexin–neuroligin signaling in synapse development

Synapse formation and clustering of neuroligin-2 in the absence of GABA A receptors

Analysis of splice variants for the C. elegans orthologue of human neuroligin reveals a developmentally regulated transcript

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Synapse formation and clustering of neuroligin-2 in the absence of GABA _A receptors