The dynamics of synaptic scaffolds

Specht, Christian G.; Triller, Antoine

doi:10.1002/bies.20831

Cited by 41 publications

(107 citation statements)

References 123 publications

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“…AMPA receptors interact with multiple accessory proteins (e.g., TARP and cornichon) (Straub and Tomita, 2012) and are localized to the postsynaptic density, where they interact with scaffolding and other proteins (Specht and Triller, 2008;Huganir and Nicoll, 2013). AMPA receptors bind to and are activated by synaptically released glutamate, which triggers the rapid opening of a cation conductance.…”

Section: Ampa-selective Glutamate Receptorsmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

186

176

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The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

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Section: Ampa-selective Glutamate Receptorsmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

186

176

View full text Add to dashboard Cite

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“…It is thought [1] that the stability and plasticity of synapses constitute part of the physiological basis for memory formation and learning. One of the key regulators of signal transmission across chemical synapses are receptor molecules [1][2][3][4] concentrated in postsynaptic membrane domains opposite presynaptic terminals. Synaptic receptor molecules transiently bind to neurotransmitter molecules released by the presynaptic cell.…”

Section: Introductionmentioning

confidence: 99%

“…Synaptic receptor molecules transiently bind to neurotransmitter molecules released by the presynaptic cell. The strength of the transmitted signal-the so-called postsynaptic potential-depends on the number of receptor molecules present in the postsynaptic domain [1,3], and activity-induced variation in the concentration of synaptic receptors is one of the mechanisms governing postsynaptic plasticity [5][6][7]. A fundamental question in neurobiology is as follows: What determines the number of receptor molecules in a postsynaptic domain?…”

Section: Introductionmentioning

confidence: 99%

Self-assembly and plasticity of synaptic domains through a reaction-diffusion mechanism

et al. 2015

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Signal transmission across chemical synapses relies crucially on neurotransmitter receptor molecules, concentrated in postsynaptic membrane domains along with scaffold and other postsynaptic molecules. The strength of the transmitted signal depends on the number of receptor molecules in postsynaptic domains, and activity-induced variation in the receptor number is one of the mechanisms of postsynaptic plasticity. Recent experiments have demonstrated that the reaction and diffusion properties of receptors and scaffolds at the membrane, alone, yield spontaneous formation of receptor-scaffold domains of the stable characteristic size observed in neurons. On the basis of these experiments we develop a model describing synaptic receptor domains in terms of the underlying reaction-diffusion processes. Our model predicts that the spontaneous formation of receptor-scaffold domains of the stable characteristic size observed in experiments depends on a few key reactions between receptors and scaffolds. Furthermore, our model suggests novel mechanisms for the alignment of preand postsynaptic domains and for short-term postsynaptic plasticity in receptor number. We predict that synaptic receptor domains localize in membrane regions with an increased receptor diffusion coefficient or a decreased scaffold diffusion coefficient. Similarly, we find that activity-dependent increases or decreases in receptor or scaffold diffusion yield a transient increase in the number of receptor molecules concentrated in postsynaptic domains. Thus, the proposed reaction-diffusion model puts forth a coherent set of biophysical mechanisms for the formation, stability, and plasticity of molecular domains on the postsynaptic membrane.

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“…Interactions of receptors with cytoplasmic scaffold proteins are responsible for the confinement and accumulation of receptors in front of presynaptic release sites (for review, see Specht and Triller, 2008). Among these proteins, gephyrin is the core molecule for anchoring and stabilizing glycine and GABA A receptors (GlyR and GABA A R) at inhibitory postsynaptic sites (Kirsch et al, 1993;Meier et al, 2001;Fritschy et al, 2008;Tretter et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Gephyrin Oligomerization Controls GlyR Mobility and Synaptic Clustering

Calamai

Specht²,

Heller³

et al. 2009

Journal of Neuroscience

149

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High local concentrations of glycine receptors (GlyRs) at inhibitory postsynaptic sites are achieved through their binding to the scaffold protein gephyrin. The N-and C-terminal domains of gephyrin are believed to trimerize and dimerize, respectively, thus contributing to the formation of submembranous gephyrin clusters at synapses. GlyRs are associated with gephyrin also at extrasynaptic locations. We have investigated how gephyrin oligomerization influences GlyR dynamics and clustering in COS-7 cells and in cultured spinal cord neurons. To this aim, we have expressed isolated N-and C-terminal domains of gephyrin that interfere with the oligomerization of the full-length protein. We also studied the effect of an endogenous splice variant, ge(2,4,5), with a decreased propensity to trimerize. A reduction of the size and number of gephyrin-GlyR clusters was found in cells expressing the various interfering gephyrin constructs. Using fluorescence recovery after photobleaching, we studied the exchange kinetics of synaptic gephyrin clusters. Real-time singleparticle tracking was used to analyze the mobility of GlyRs. We found that all the tested constructs displayed faster rates of recovery than wild-type gephyrin and increased the mobility of extrasynaptic receptors, showing that gephyrin-gephyrin interactions modulate the lateral diffusion of GlyRs. Furthermore, we observed an inverse correlation between GlyR diffusion properties and gephyrin cluster size that depended on the number of binding sites blocked by the different constructs. Since alterations in the oligomerization properties of gephyrin are related to the dynamics of GlyRs, the gephyrin splice variant ge(2,4,5) may be implicated in the modulation of synaptic strength.

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The dynamics of synaptic scaffolds

Cited by 41 publications

References 123 publications

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Self-assembly and plasticity of synaptic domains through a reaction-diffusion mechanism

Gephyrin Oligomerization Controls GlyR Mobility and Synaptic Clustering

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