Neurexin-3 subsynaptic densities are spatially distinct from Neurexin-1 and essential for excitatory synapse nanoscale organization in the hippocampus

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 5, 2023

Abstract Proteins critical for synaptic transmission are non-uniformly distributed and assembled into regions of high density called subsynaptic densities (SSDs) that transsynaptically align in nanocolumns. Neurexin-1 neurexin-3 essential presynaptic adhesion molecules non-redundantly control NMDAR- AMPAR-mediated transmission, respectively, via transsynaptic interactions with distinct postsynaptic ligands. Despite their functional relevance, fundamental questions regarding the nanoscale properties individual neurexins, influence on organization excitatory synapses mechanisms controlling how neurexins engage precise unknown. Using Double Helix 3D dSTORM neurexin mouse models, we identify as a molecule regulates synapse nano-organization hippocampus. Furthermore, endogenous neurexin-1 form discrete non-overlapping SSDs enriched opposite Thus, may explain signal parallel to govern different properties.

Language: Английский

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Structure and function meet at the nicotinic acetylcholine receptor-lipid interface

Pharmacological Research, Journal Year: 2023, Volume and Issue: 190, P. 106729 - 106729

Published: March 15, 2023

The nicotinic acetylcholine receptor (nAChR) is a transmembrane protein that mediates fast intercellular communication in response to the endogenous neurotransmitter acetylcholine. It best characterized and archetypal molecule superfamily of pentameric ligand-gated ion channels (pLGICs). As typical macromolecule, it interacts extensively with its vicinal lipid microenvironment. Experimental evidence provides wealth information on receptor-lipid crosstalk: nAChR exerts influence immediate membrane environment conversely, moiety modulates ligand binding, affinity state transitions gating translocation functions protein. Recent cryogenic electron microscopy (cryo-EM) studies have unveiled occurrence sites for phospholipids cholesterol lipid-exposed regions neuronal electroplax nAChRs, confirming early spectroscopic labeling demonstrating close contact molecules segments. This new data structural support postulated "lipid sensor" ability displayed by outer ring M4 domains their modulatory role function, as we decade ago. Borrowing from nAChR, (muscle-type) receptor, exploiting now possible achieve an improved depiction these sites. In combination site-directed mutagenesis, single-channel electrophysiology, molecular dynamics studies, delivers more comprehensive portrayal lipid-sensitive loci, providing mechanistic explanations modulate properties raising possibility targetting them disease.

Language: Английский

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Presynaptic nanoscale components of retrograde synaptic signaling

Science Advances, Journal Year: 2024, Volume and Issue: 10(22)

Published: May 29, 2024

While our understanding of the nanoscale architecture anterograde synaptic transmission is rapidly expanding, qualitative and quantitative molecular principles underlying distinct mechanisms retrograde communication remain elusive. We show that a particular form tonic cannabinoid signaling essential for setting target cell-dependent variability. It does not require activity two major endocannabinoid-producing enzymes. Instead, by developing workflow physiological, anatomical, measurements at same unitary synapse, we demonstrate stoichiometric ratio type 1 receptors (CB

Language: Английский

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The molecular signals that regulate activity-dependent synapse refinement in the brain

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 79, P. 102692 - 102692

Published: Feb. 17, 2023

Language: Английский

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Astrocytic Neuroligin-3 influences gene expression and social behavior, but is dispensable for synapse number

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: July 13, 2024

Abstract Neuroligin-3 ( Nlgn3 ) is an autism-associated cell-adhesion molecule that interacts with neurexins and robustly expressed in both neurons astrocytes. Neuronal essential regulator of synaptic transmission but the function astrocytic largely unknown. Given high penetrance mutations autism emerging role astrocytes neuropsychiatric disorders, we here asked whether might shape neural circuit properties cerebellum similar to neuronal . Imaging tagged protein produced by CRISPR/Cas9-mediated genome editing showed enriched cell body not fine processes cerebellar (Bergmann glia). Astrocyte-specific knockout did detectably alter number synapses, transmission, or astrocyte morphology mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift gene expression among multiple types after deletion Hence, contrast , involved shaping synapses may modulate specific brain areas.

Language: Английский

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Bridging the translational gap: what can synaptopathies tell us about autism?

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: June 27, 2023

Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved biology. Synaptopathies are commonly developmental delay may be range neuropsychiatric outcomes. Altered biology suggested by both preclinical studies based evidence differences early brain structural development altered glutamatergic GABAergic neurotransmission potentially perturbing excitatory inhibitory balance. This review focusses NRXN-NLGN-SHANK pathway, assembly, trans-synaptic signalling, functioning. We provide an overview insights from pathway. Concentrating NRXN1 deletion SHANK3 mutations, we discuss emerging understanding electrophysiology induced pluripotent stem cells (iPSC) models derived individuals neuroimaging behavioural findings animal Nrxn1 Shank3 key regarding features, phenotypes human synaptopathies. The identification molecular-based biomarkers aims advance targeted therapeutic treatments. However, it remains challenging translate iPSC interpret features. existing challenges synaptopathy research, potential solutions align methodologies across research. Bridging translational gap between will necessary understand biological mechanisms, identify therapies, ultimately progress towards personalised approaches for complex such as autism.

Language: Английский

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Neuroligin-3 activates Akt-dependent Nrf2 cascade to protect osteoblasts from oxidative stress

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 208, P. 807 - 819

Published: Sept. 27, 2023

Language: Английский

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Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 12, 2024

Abstract Nanoscale protein organization within the active zone (AZ) and post-synaptic density (PSD) influences synaptic transmission. Nanoclusters of presynaptic Munc13-1 are associated with readily releasable pool size neurotransmitter vesicle priming, while postsynaptic PSD-95 nanoclusters coordinate glutamate receptors across from release sites to control their opening probability. Nanocluster number, size, vary between synapse types development plasticity, supporting a wide range functional states at synapse. Whether or how themselves this critical architecture remains unclear. One prominent PSD molecular complex is NMDA receptor (NMDAR). NMDARs several modes signaling synapses, giving them potential influence through direct interactions signaling. We found that loss results in larger synapses contain smaller, denser, more numerous nanoclusters. Intriguingly, NMDAR also generates retrograde reorganization zone, resulting nanoclusters, which aligned Together, these changes nanostructure predict stronger AMPA receptor-mediated transmission absence NMDARs. Notably, prolonged antagonism activity increases it does not fully recapitulate trans-synaptic effects. Thus, our confirm play an important role maintaining pre- suggest both decreased expression suppressed may exert distinct effects on function, yet unique architectural mechanisms. Significance Statement Synaptic shaped by coordination ensembles required for retention, but Using state-of-the-art super-resolution microscopy, we report excitatory alters nano-organizational features. pharmacological features, without mimicking knockout. This suggests presence organization. Because disease decrease function receptors, nanostructural contribute status disorders.

Language: Английский

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Structural and functional reorganization of inhibitory synapses by activity-dependent cleavage of neuroligin-2

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(18)

Published: April 24, 2024

Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating strength excitatory synapses. However, molecular mechanism underlying this nanostructure inhibitory synapses still remains unclear and its impact on synapse function physiological or pathological contexts not been demonstrated. In study, we utilized an engineered proteolysis technique to investigate effects acute cleavage neuroligin-2 (NL2) transmission. Our results show rapid NL2 led impaired transmission by reducing both neurotransmitter release probability quantum size. These changes were attributed dispersion RIM1/2 GABA A receptors weakened spatial alignment between them at subsynaptic scale, as observed through superresolution imaging model simulations. Importantly, found endogenous undergoes MMP9-dependent during epileptic activities, which further exacerbates decrease Overall, our study demonstrates significant structural reorganization unveils ongoing modulation mature GABAergic active response hyperactivity.

Language: Английский

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Combinatorial expression of neurexins and LAR-type phosphotyrosine phosphatase receptors instructs assembly of a cerebellar circuit

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 17, 2023

Abstract Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses thereby control information processing power neural circuits. SAMs are broadly expressed in brain, suggesting that they may instruct synapse formation specification via a combinatorial logic. Here, we generate sextuple conditional knockout mice targeting all members two major families presynaptic SAMs, Neurexins leukocyte common antigen-related-type receptor phospho-tyrosine phosphatases (LAR-PTPRs), which together account for majority known trans-synaptic complexes. Using formed by cerebellar Purkinje cells onto deep nuclei as model system, confirm LAR-PTPRs themselves not essential assembly. The deletion both neurexins LAR-PTPRs, however, decreases Purkinje-cell on nuclei, output pathway Consistent with this finding, combined but separate deletions impair motor behaviors. Thus, required assembly circuit.

Language: Английский

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