The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin

Meyer, Guido; Varoqueaux, Frédérique; Neeb, Antje; Oschlies, Melanie; Brose, Nils

doi:10.1016/j.neuropharm.2004.06.023

Cited by 175 publications

(151 citation statements)

References 65 publications

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“…For NL2, interactions through the cytoplasmic collybistin-gephyrin complex contribute to GABA-A receptor recruitment to perisomatic synapses (41). For NL1 at glutamatergic synapses, it has been puzzling that all NL isoforms bind indiscriminately to a broad range of glutamatergic scaffolding molecules that would connect them to glutamatergic neurotransmitter receptors without apparent selectivity (15,42). Our findings indicate that not intracellular sequences but the extracellular ChE domain of NL1 plays an instructive role in selective coupling to NMDARs.…”

Section: Neuroligin Isoform Specificity In the Association With Neuromentioning

confidence: 86%

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Budreck

Kwon

Jung

et al. 2012

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

164

161

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Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cisinteractions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.synapse | neurotranmitter receptor | neurexin N MDA receptors (NMDARs) are key regulators of the development of neural circuits and synaptic plasticity (1, 2). In humans, perturbation of NMDAR function results in psychotic conditions, and genetic animal models with altered NMDAR activity exhibit phenotypes related to cognitive disorders such as schizophrenia and autism (3-5). Activity-dependent recruitment of NMDARs to synapses controls certain forms of synaptic plasticity (6, 7). However, the molecular mechanisms underlying the recruitment and physical tethering of NMDAR complexes at synapses are incompletely understood.Neuroligin-1 (NL1), one of four postsynaptic neuroligin adhesion molecules (NL1, 2, 3, 4), contributes to NMDAR regulation (8, 9). In cultured neurons, overexpression of NL1 promotes clustering of synaptic NMDARs (8), and NL1 KO mice show decreases in NMDAR-dependent excitatory postsynaptic currents (NMDAR EPSCs) (9-11). A major question in understanding neuroligin function is how specific isoforms couple to specific neurotransmitter receptors (12, 13). NMDARs were recovered in coimmunoprecipitations with NL proteins, indicating a potential complex formation, although in those experiments, no NL isoform-specificity was apparent (14). One candidate link between NLs and glutamate receptors is through postsynaptic scaffolding molecules such as postsynaptic density 95 (PSD95) (15, 16). However, all NL isoforms contain PSD95 binding sites, and NMDARs and PSD95 were recruited to NL1 with different time courses (14).Our results demonstrate that NL1 controls synaptic abundance of NMDAR via NL1-specific extracellular determinants. Loss of these interactions results in impairment of NMDAR-mediated transmission and synaptic plasticity. Our findings uncover an unexpected mode of NL1-NMDAR coupling and demonstrate a key role for the NL1 adhesion protein in the physical incorporation and retention of NMDAR at glutamatergic synapses.Results NL1-Specific Recruitment of NMDARs Does Not Require PSD95. We examined the specificity of molecular coupling of NL isoforms (NL1, 2, 3) to NMDARs by NL overexpression in cultured hippocampal neurons. NL1 increased the density of clusters of the NMDAR subunits GluN1, GluN2A, and GluN...

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Section: Neuroligin Isoform Specificity In the Association With Neuromentioning

confidence: 86%

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Budreck

Kwon

Jung

et al. 2012

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

164

161

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“…Neuroligins bind to several postsynaptic components of glutamatergic synapses: PDZ-domain scaffolding proteins such as PSD-95 and related MAGUKs, S-SCAM and related MAGIs, and probably also Shank, PICK1, GOPC and SPAR [29][30][31]. Thus, it came as a surprise when two groups [3•,32] independently found that neuroligin 2 concentrates not at glutamate postsynaptic sites but at GABA postsynaptic sites.…”

Section: Synaptic Localization and Interacting Partnersmentioning

confidence: 99%

Neurexin–neuroligin signaling in synapse development

Craig

Kang

2007

Current Opinion in Neurobiology

562

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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“…SHANK3 is a scaffolding protein of the postsynaptic density (PSD), which binds to the NLGN, and known to regulate the structural organization of dendritic spines (Boeckers et al 2002;Meyer et al 2004). Durand et al (2007) sequenced the coding sequence of SHANK3 in 227 individuals with ASD and showed that mutations, or loss of one copy of the gene, are associated with autism, whereas the presence of an extra copy might be associated with Asperger syndrome.…”

Section: Atypical Synapses In Autism Spectrum Disorders?mentioning

confidence: 99%

The Possible Interplay of Synaptic and Clock Genes in Autism Spectrum Disorders

Bourgeron¹

2007

Cold Spring Harbor Symposia on Quantitative Biology

163

124

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Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by deficits in social communication, absence or delay in language, and stereotyped and repetitive behaviors. Results from genetic studies reveal one pathway associated with susceptibility to ASD, which includes the synaptic cell adhesion molecules NLGN3, NLGN4, and NRXN1 and a postsynaptic scaffolding protein SHANK3. This protein complex is crucial for the maintenance of functional synapses as well as the adequate balance between neuronal excitation and inhibition. Among the factors that could modulate this pathway are the genes controlling circadian rhythms. Indeed, sleep disorders and low melatonin levels are frequently observed in ASD. In this context, an alteration of both this synaptic pathway and the setting of the clock would greatly increase the risk of ASD. In this chapter, I report genetic and neurobiological findings that highlight the major role of synaptic and clock genes in the susceptibility to ASD. On the basis of these lines of evidence, I propose that future studies of ASD should investigate the circadian modulation of synaptic function as a focus for functional analyses and the development of new therapeutic strategies.

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The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin

Cited by 175 publications

References 65 publications

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling

Neurexin–neuroligin signaling in synapse development

The Possible Interplay of Synaptic and Clock Genes in Autism Spectrum Disorders

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