Presynaptic Neurexin-3 Alternative Splicing trans-Synaptically Controls Postsynaptic AMPA Receptor Trafficking

Aoto, Jason; Martinelli, David C.; Malenka, Robert C.; Tabuchi, Katsuhiko; Südhof, Thomas C.

doi:10.1016/j.cell.2013.05.060

Cited by 263 publications

(383 citation statements)

References 59 publications

(106 reference statements)

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“…In support of this supposition, LRRTM4 was recently annotated as an AMPA receptor constituent in a multiepitope proteomic analysis (35). Moreover, presynaptic neurexin-3 was recently reported to control postsynaptic AMPA receptor trafficking through direct binding to LRRTM2 (36); thus, it is probable that presynaptic PTPσ also does so by behaving similarly. Directly exploring the function of PTPσ/GPCs/LRRTM4 synaptic adhesion pathways in vivo will ultimately require systematic characterization of conditional knockout mice lacking PTPσ and/or GPCs.…”

Section: Discussionmentioning

confidence: 91%

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Pramanik

et al. 2015

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

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Leukocyte common antigen-related receptor protein tyrosine phosphatases-comprising LAR, PTPδ, and PTPσ-are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding-defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.PTPσ | glypican | LRRTM4 | synaptic cell adhesion | heparan sulfate

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Section: Discussionmentioning

confidence: 91%

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Pramanik

et al. 2015

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

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“…In addition, research has identified several molecules, mostly ion channels and receptors, which are functionally impaired when Nrxn expression is altered. Nrxn variants have been found to affect voltage-dependent calcium channels (9,10), GABA A R (7, 37), NMDAR (44), GABA B R (36,45), nicotinergic acetylcholine receptors (69), and AMPAR (47). These ionotropic and metabotropic receptors represent "target molecules" of Nrxn that may include some physical association, but it appears unlikely that the functional link to all these requires stable protein-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

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

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Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA B R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA B R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA B R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA A R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA B R and postsynaptic GABA A R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA A R and GABA B R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. synaptic transmission | thalamus | autism | neuroligin | ultrastructure

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“…11 Each neurexin can bind to a small number of postsynaptic ligands, including neuroligins, cerebellins, and LRRTMs 11,19 ; neurexin-3a binds specifically to LRRTM2. 20,21 The serum and CSF of our 5 patients contained antibodies against neurexin-3a but not LRRTM2.…”

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confidence: 87%

Human neurexin-3α antibodies associate with encephalitis and alter synapse development

et al. 2016

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Objective: To report a novel autoimmune encephalitis in which the antibodies target neurexin-3a, a cell adhesion molecule involved in the development and function of synapses.Methods: Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques.Results: Immunoprecipitation and cell-based assays identified neurexin-3a as the autoantigen of patients' antibodies. All 5 patients (median age 44 years, range 23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7-17 to patients' IgG showed a decrease of neurexin-3a clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients' IgG. Neuronal survival, dendritic morphology, and spine density were unaffected. Conclusion:Neurexin-3a autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3a and alter synapse development. Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Studies from different countries and a recent meta-analysis showed that in about 40% of patients with encephalitis the cause is never identified.1,2 Without reliable biomarkers, a response to empiric immunotherapy is frequently used to support that the disorder is immune-mediated, but a lack of response does not rule out an immune-mediated pathogenesis. For example, approximately 40% of patients with anti-NMDA receptor (NMDAR) encephalitis fail first-line immunotherapy (steroids, plasma exchange, or IV immunoglobulin [IVIg]) and require second-line therapies (rituximab or cyclophosphamide).3,4 However, second-line therapies are rarely used in encephalitis of unclear cause unless evidence of autoimmunity is provided. In this setting, the demonstration of autoantibodies to neuronal cell

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Presynaptic Neurexin-3 Alternative Splicing trans-Synaptically Controls Postsynaptic AMPA Receptor Trafficking

Cited by 263 publications

References 59 publications

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Human neurexin-3α antibodies associate with encephalitis and alter synapse development

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