Neurexins regulate presynaptic GABAB-receptors at central synapses

Luo, Fujun; Sclip, Alessandra; Merrill, Sean; Südhof, Thomas C.

doi:10.1038/s41467-021-22753-5

Cited by 34 publications

(34 citation statements)

References 63 publications

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“…Initial studies of individual or combined deletions of Nrxn1α, Nrxn2α, and Nrxn3α in mice (with retained expression of β-neurexins) revealed that α-neurexins are essential for synaptic transmission and survival, and that their combined deletion causes a decrease in release probability but does not induce major changes in excitatory synapse numbers (32)(33)(34). These studies showed that the deletions of α-neurexins lower the activity of presynaptic voltage-gated Ca 2+ channels, a finding that was extended in subsequent studies to deletions of all α-and β-neurexins (35)(36)(37).…”

Section: Introductionmentioning

confidence: 81%

“…Following the procedures previously described in ( 56 ), dSTORM images were recorded with a Vutara SR 352 (Bruker Nanosurfaces Inc., Madison, WI) commercial microscope based on single-molecule localization biplane technology ( 37 , 57 , 58 ). Twenty-five–micrometer–thick hippocampal slices containing the CA1 region were prepared as described and labeled with Homer1 (1:1000; rabbit, Millipore, catalog no.…”

Section: Methodsmentioning

confidence: 99%

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Neurexin-2: An inhibitory neurexin that restricts excitatory synapse formation in the hippocampus

et al. 2023

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Neurexins are widely thought to promote synapse formation and to organize synapse properties. Here we found that in contrast to neurexin-1 and neurexin-3, neurexin-2 unexpectedly restricts synapse formation. In the hippocampus, constitutive or neuron-specific deletions of neurexin-2 nearly doubled the strength of excitatory CA3➔CA1 region synaptic connections and markedly increased their release probability. No effect on inhibitory synapses was detected. Stochastic optical reconstruction microscopy (STORM) superresolution microscopy revealed that the neuron-specific neurexin-2 deletion elevated the density of excitatory CA1 region synapses nearly twofold. Moreover, hippocampal neurexin-2 deletions also increased synaptic connectivity in the CA1 region when induced in mature mice and impaired the cognitive flexibility of spatial memory. Thus, neurexin-2 controls the dynamics of hippocampal synaptic circuits by repressing synapse assembly throughout life, a restrictive function that markedly differs from that of neurexin-1 and neurexin-3 and of other synaptic adhesion molecules, suggesting that neurexins evolutionarily diverged into opposing pro- and antisynaptogenic organizers.

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Section: Introductionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Neurexin-2: An inhibitory neurexin that restricts excitatory synapse formation in the hippocampus

et al. 2023

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“…Two-color super-resolution imaging further reveals that mGluR4 forms nanoclusters within active zones of cerebellar PFs and co-localizes with CaV2.1 channels and Munc18 (Siddig et al, 2020 ). Similarly, presynaptic GABA B -receptors are clustered within active zones and play a critical role in regulating CaV channel function (Lujan et al, 2004 , 2018 ; Luo et al, 2021 ). By contrast, EM and super-resolution imaging show that CB1 receptors are excluded from active zones, but distributed uniformly in the extrasynaptic region of the nerve terminal (Nyiri et al, 2005 ; Dudok et al, 2015 ).…”

Section: Nanoscale Modulation Of Cav Channels By G-protein Coupled Re...mentioning

confidence: 99%

Diverse organization of voltage-gated calcium channels at presynaptic active zones

Zhang

Jiang

Luo

2022

Front. Synaptic Neurosci.

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Synapses are highly organized but are also highly diverse in their organization and properties to allow for optimizing the computing power of brain circuits. Along these lines, voltage-gated calcium (CaV) channels at the presynaptic active zone are heterogeneously organized, which creates a variety of calcium dynamics profiles that can shape neurotransmitter release properties of individual synapses. Extensive studies have revealed striking diversity in the subtype, number, and distribution of CaV channels, as well as the nanoscale topographic relationships to docked synaptic vesicles. Further, multi-protein complexes including RIMs, RIM-binding proteins, CAST/ELKS, and neurexins are required for coordinating the diverse organization of CaV channels at the presynaptic active zone. In this review, we highlight major advances in the studies of the functional organization of presynaptic CaV channels and discuss their physiological implications for synaptic transmission and short-term plasticity.

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“…Primarily, Nrxs influence components of the presynaptic machinery and synaptic functional efficiency. For example, Nrx deletion results in the loss of presynaptic active-zone GABARs, decreasing the sensitivity of neurotransmitter release to GABAR activation at both excitatory and inhibitory synapses [ 22 ]. Given the importance of presynaptic GABARs in the nucleation of signaling complexes that control the release of neurotransmitters, the ability of Nrxs to regulate these receptors enables them to further govern synaptic transmission and plasticity from the presynaptic perspective [ 23 , 24 , 25 ].…”

Section: The Neurexin–neuroligin Mediated Trans-synaptic Modulationmentioning

confidence: 99%

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

Guo

Guan

et al. 2022

Cells

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Synapses serve as the interface for the transmission of information between neurons in the central nervous system. The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx–Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx–Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx–Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx–Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain.

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Neurexins regulate presynaptic GABAB-receptors at central synapses

Cited by 34 publications

References 63 publications

Neurexin-2: An inhibitory neurexin that restricts excitatory synapse formation in the hippocampus

Neurexin-2: An inhibitory neurexin that restricts excitatory synapse formation in the hippocampus

Diverse organization of voltage-gated calcium channels at presynaptic active zones

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

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