α-Neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction

Sons, Michèle S.; Busche, N.; Strenzke, Nicola; Moser, Tobias; Ernsberger, Uwe; Mooren, Frank-Christoph; Zhang, W.; Ahmad, Mohiuddin; Steffens, Heinz; Schomburg, E. D.; Plomp, J. J.; Missler, Markus

doi:10.1016/j.neuroscience.2005.11.040

Cited by 60 publications

(48 citation statements)

References 66 publications

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“…These observations suggest that NRX regulates activity-dependent synaptic plasticity. Similar observations have been reported in the fast-twitch diaphragm muscle of the ␣-NRX double knock-out mouse, which indicates that presynaptic efficacy but not presynaptic homeostatic plasticity is normal under basal conditions (46). Deficits in both the presynaptic neurotransmitter release machinery and the postsynaptic neurotransmitter receptors may cause rapid short term synaptic depression (31,37).…”

Section: Nrx Facilitates Repetitive Synaptic Vesicle Release-previ-supporting

confidence: 68%

The Neurexin/N-Ethylmaleimide-sensitive Factor (NSF) Interaction Regulates Short Term Synaptic Depression

Tian

et al. 2015

Journal of Biological Chemistry

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Background: Neurexins (NRXs) are cell adhesion molecules and regulate synapse formation and synaptic transmission. Results: NRX associates with NSF in vivo, and the absence of NRX/NSF interaction results in abnormal distribution and impaired function of NSF. Conclusion: NRX/NSF interaction facilitates NSF recruitment and subsequent SNARE complex disassembly. Significance: Neurexin regulates the presynaptic exocytotic machinery.

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Section: Nrx Facilitates Repetitive Synaptic Vesicle Release-previ-supporting

confidence: 68%

The Neurexin/N-Ethylmaleimide-sensitive Factor (NSF) Interaction Regulates Short Term Synaptic Depression

Tian

et al. 2015

Journal of Biological Chemistry

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“…Consistently, cell culture assays revealed transsynaptic binding of Nrxns to postsynaptic neuroligin, resulting in the recruitment of presynaptic proteins (Scheiffele et al, 2000;Dean et al, 2003). Similarly consistent, studies in null-mutant mice revealed that ␣-Nrxns play a role in presynaptic Ca 2ϩ -dependent neurotransmitter release at excitatory and inhibitory synapses (Missler et al, 2003;Zhang et al, 2005), and in Ca 2ϩ -dependent release from NMJ and endocrine melanotrophs where no neuronal postsynaptic terminals exists Sons et al, 2006).…”

Section: Discussionmentioning

confidence: 58%

Polarized Targeting of Neurexins to Synapses Is Regulated by their C-Terminal Sequences

Fairless¹,

Masius²,

Rohlmann³

et al. 2008

J. Neurosci.

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Two families of cell-adhesion molecules, predominantly presynaptic neurexins and postsynaptic neuroligins, are important for the formation and functioning of synapses in the brain, and mutations in several genes encoding these transmembrane proteins have been found in autism patients. However, very little is known about how neurexins are targeted to synapses and which mechanisms regulate this process. Using various epitope-tagged neurexins in primary hippocampal neurons of wild-type and knock-out mice in vitro and in transgenic animals in vivo, we show that neurexins are trafficked throughout neurons via transport vesicles and the plasma membrane insertion of neurexins occurs preferentially in the axonal/synaptic compartment. We also observed that exit of neurexins from the ER/Golgi and correct targeting require their PDZ-binding motif at the C terminus, whereas two presumptive ER retention signals are inactive. The ubiquitous presence of neurexin-positive transport vesicles and absence of bassoon colabeling demonstrate that these carriers are not active zone precursor vesicles, but colocalization with CASK, RIM1␣, and calcium channels suggests that they may carry additional components of the exocytotic machinery. Our data indicate that neurexins are delivered to synapses by a polarized and regulated targeting process that involves PDZ-domain mediated interactions, suggesting a novel pathway for the distribution of neurexins and other synaptic proteins.

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“…In fact, we reported previously that the GABA B R-mediated modulation of Ca V 2.2 channels, required for its effect on vesicle release (58), was also impaired at excitatory brainstem synapses of α-Nrxn KO mice (45). Even more importantly, α-Nrxn is abundantly expressed in glutamatergic neurons as well (12) and has unequivocal effects on release from excitatory synapses (9,44,46,78). These results cannot be explained by a simple association of α-Nrxn with inhibitory and, of β-Nrxn with excitatory terminals as cautioned before (37).…”

Section: Discussionmentioning

confidence: 91%

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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α-Neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction

Cited by 60 publications

References 66 publications

The Neurexin/N-Ethylmaleimide-sensitive Factor (NSF) Interaction Regulates Short Term Synaptic Depression

The Neurexin/N-Ethylmaleimide-sensitive Factor (NSF) Interaction Regulates Short Term Synaptic Depression

Polarized Targeting of Neurexins to Synapses Is Regulated by their C-Terminal Sequences

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

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