Control of Excitatory and Inhibitory Synapse Formation by Neuroligins

Chih, Ben; Engelman, Holly S.; Scheiffele, Peter

doi:10.1126/science.1107470

Cited by 643 publications

(789 citation statements)

References 27 publications

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“…At the synapse, presynaptic and postsynaptic membranes are linked together by a variety of adhesion molecules 1 . Two adhesion molecules that have been implicated in the establishment and maturation of synaptic contacts are neuroligins, which are postsynaptic proteins, and neurexins, which are presynaptic proteins [2][3][4][5][6][7] . Polymorphisms in neuroligin and neurexin genes have been associated with several cases of cognitive disorders such as autism and mental retardation [8][9][10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Chen

Liu

Shim

et al. 2007

Nat Struct Mol Biol

147

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The heterophilic synaptic adhesion molecules, neuroligins and neurexins, are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca 2+ -dependent and regulated by alternative splicing. We report a 2.4Å structure of the complex between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin 1β (NX1β) LNS (laminins, neurexins, and sex hormone-binding globulin-like) domain. The structure reveals a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca 2+ -mediated, and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data support a mechanism where splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1β interface. Mapping neuroligin mutations implicated in autism indicates most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

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Section: Introductionmentioning

confidence: 99%

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Chen

Liu

Shim

et al. 2007

Nat Struct Mol Biol

147

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“…A naive hypothesis is that integration of greater individual synaptic efficacy might lead to hyperexcitability. However, some mechanisms appear to modulate overall activity by balancing excitatory and inhibitory inputs to prevent epileptic bursting (Chih et al, 2005;Koester and Johnston, 2005). Turigiano's group has found ranges for balancing of inward and outward currents that prevent bursting during changes in input excitation (Turigiano et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Added astroglia promote greater synapse density and higher activity in neuronal networks

2007

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Astroglia are known to potentiate individual synapses, but their contribution to networks is unclear.Here we examined the effect of adding either astroglia or media conditioned by astroglia on entire networks of rat hippocampal neurons cultured on microelectrode arrays. Added astroglia increased spontaneous spike rates nearly two-fold and glutamate-stimulated spiking by six-fold, with desensitization eliminated for bath addition of 25 μM glutamate. Astrocyte-conditioned medium partly mimicked the effects of added astroglia. Bursting behavior was largely unaffected by added astroglia except with added glutamate. Addition of the GABA A receptor antagonist bicuculline also increased spike rates but with more subtle differences between networks without or with added astroglia. This indicates that networks without added astroglia were inhibited greatly. In all conditions, the log-log distribution of spike rates fit well to linear distributions over three orders of magnitude. Networks with added astroglia shifted consistently toward higher spike rates. Immunostaining for GFAP revealed a linear increase with added astroglia, which also increased neuronal survival. The increased spike rates with added astroglia correlated with a 1.7-fold increase in immunoreactive synaptophysin puncta, and increases of six-fold for GABA Aβ , two-fold for NMDA-R1 and two-fold for Glu-R1 puncta, with receptor clustering that indicated synaptic scaling. Together, these results indicate that added astroglia increase the density of synapses and receptors, and facilitate higher spike rates for many elements in the network. These effects are reproduced by glia-conditioned media, with the exception of glutamate-mediated transmission.

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“…In addition, NL2−/− mice display a selective decrease in the number of inhibitory synapses in the postnatal neocortex [55]. Overexpression of NL2 in cultured neurons increases the density of glutamatergic and GABAergic terminals but has a higher activity towards GABAergic axons [56]. At a functional level, NL2 overexpression selectively increases the amplitude of inhibitory postsynaptic currents suggesting that the postsynaptic coupling of this neuroligin isoform is specific for inhibitory synapses [55].…”

Section: Trans-synaptic Signaling By the Neuroligin-neurexin Adhesionmentioning

confidence: 99%

GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development

Huang

Scheiffele

2008

Current Opinion in Neurobiology

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GABA-mediated synaptic inhibition is crucial in neural circuit operations. In mammalian brains, the development of inhibitory synapses and innervation patterns is often a prolonged postnatal process, regulated by neural activity. Emerging evidence indicates that GABA acts beyond inhibitory transmission and regulates inhibitory synapse development. Indeed, GABA A receptors not only function as chloride channels that regulate membrane voltage and conductance but also play structural roles in synapse maturation and stabilization. The link from GABA A receptors to post-and pre-synaptic adhesion is likely mediated, in part, by neuroligin-reurexin interactions, which are potent in promoting GABAergic synapse formation. Therefore, similar to glutamate signaling at excitatory synapse, GABA signaling may coordinate maturation of pre-and postsynaptic sites at inhibitory synapses. Defining the many steps from GABA signaling to receptor trafficking/stability and neuroligin function will provide further mechanistic insights into activitydependent development and possibly plasticity of inhibitory synapses.

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Control of Excitatory and Inhibitory Synapse Formation by Neuroligins

Cited by 643 publications

References 27 publications

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Added astroglia promote greater synapse density and higher activity in neuronal networks

GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development

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