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Cell Reports Oct 2023Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction....
Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction. After passive transfer of patients' cerebrospinal fluid or human monoclonal anti-GluN1-autoantibodies in mice, we find a disrupted excitatory-inhibitory balance resulting from CA1 neuronal hypoexcitability, reduced AMPA receptor (AMPAR) signaling, and faster synaptic inhibition in acute hippocampal slices. Functional alterations are also reflected in widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. NMDAR-Abs amplify network γ oscillations and disrupt θ-γ coupling. A data-informed network model reveals that lower AMPAR strength and faster GABA receptor current kinetics chiefly account for these abnormal oscillations. As predicted in silico and evidenced ex vivo, positive allosteric modulation of AMPARs alleviates aberrant γ activity, reinforcing the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-Ab-induced aberrant synaptic, cellular, and network dynamics provide conceptual insights into NMDAR-Ab-mediated pathomechanisms and reveal promising therapeutic targets that merit future in vivo validation.
Topics: Humans; Mice; Animals; Hippocampus; Synaptic Transmission; Receptors, N-Methyl-D-Aspartate; Neurons; Autoantibodies; Receptors, AMPA
PubMed: 37768823
DOI: 10.1016/j.celrep.2023.113166 -
International Journal of Molecular... Dec 2023Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory... (Review)
Review
Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.
Topics: Receptors, AMPA; Central Nervous System; Neurons; Cognition; Learning; Central Nervous System Depressants
PubMed: 38203282
DOI: 10.3390/ijms25010111 -
The Journal of Clinical Investigation Jan 2024Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of...
Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multigeneration families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine-uptake activity in cells, leading to increased extracellular glycine levels and aberrant glycinergic neurotransmission. Slc6a9 mutant zebrafish exhibited discoordination of spinal neural activities and pronounced lateral spinal curvature, a phenotype resembling human patients. The penetrance and severity of curvature were sensitive to the dosage of functional glyt1. Administration of a glycine receptor antagonist or a clinically used glycine neutralizer (sodium benzoate) partially rescued the phenotype. Our results indicate a neuropathic origin for "idiopathic" scoliosis, involving the dysfunction of synaptic neurotransmission and central pattern generators (CPGs), potentially a common cause of AIS. Our work further suggests avenues for early diagnosis and intervention of AIS in preadolescents.
Topics: Animals; Humans; Adolescent; Scoliosis; Glycine; Zebrafish; Synaptic Transmission
PubMed: 37962965
DOI: 10.1172/JCI168783 -
Cell Reports Jul 2023Ionotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and...
Ionotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and disease. We have probed the impact of synaptic glutamate levels on the two postsynaptic GluR subtypes at the Drosophila neuromuscular junction, GluRA and GluRB. We first demonstrate that GluRA and GluRB compete to establish postsynaptic receptive fields, and that proper GluR abundance and composition can be orchestrated in the absence of any synaptic glutamate release. However, excess glutamate adaptively tunes postsynaptic GluR abundance, echoing GluR scaling observed in mammalian systems. Furthermore, when GluRA vs. GluRB competition is eliminated, GluRB becomes insensitive to glutamate modulation. In contrast, GluRA is now homeostatically regulated by excess glutamate to maintain stable miniature activity, where Ca permeability through GluRA receptors is required. Thus, excess glutamate, GluR competition, and Ca signaling collaborate to selectively target GluR subtypes for homeostatic regulation at postsynaptic compartments.
Topics: Animals; Synapses; Glutamic Acid; Drosophila Proteins; Neuromuscular Junction; Drosophila; Neuronal Plasticity; Mammals
PubMed: 37436892
DOI: 10.1016/j.celrep.2023.112775 -
Experimental Physiology Jul 2023What is the topic of this review? This review focuses on the physiological role of the cytokine interleukin-1β in the CNS. What advances does it highlight?... (Review)
Review
NEW FINDINGS
What is the topic of this review? This review focuses on the physiological role of the cytokine interleukin-1β in the CNS. What advances does it highlight? Traditionally, interleukin-1β is known as a key mediator of inflammation and immunity. This review highlights the more recent findings describing how interleukin-1β signalling is required to maintain homeostasis in the CNS.
ABSTRACT
Since its discovery in the early 1940s, the interleukin-1 (IL-1) cytokine family has been associated primarily with acute and chronic inflammation. The family member IL-1β is produced by different leucocytes, endothelial cells and epithelial cells. This cytokine has been characterized as a key modulator of inflammation and innate immunity because it induces the transcription of several downstream inflammatory genes. More recently, several groups have demonstrated that IL-1β production is also required to maintain homeostasis in several organ systems. This review focuses on providing an overview of the more recently characterized role of IL-1β in the physiology of the CNS. So far, IL-1β signalling has been implicated in neuronal survival, neurite growth, synaptic pruning, synaptic transmission, neuroplasticity and neuroendocrine functions.
Topics: Humans; Cytokines; Endothelial Cells; Inflammation; Inflammation Mediators; Interleukin-1beta; Neurophysiology
PubMed: 37031383
DOI: 10.1113/EP090780 -
Neurobiology of Disease Sep 2023Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical...
Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAR subunit composition, there was a redistribution of extrasynaptic GABARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.
Topics: Mice; Animals; Diazepam; Alcoholism; Substance Withdrawal Syndrome; Receptors, GABA-A; Benzodiazepines; Brain; Synapses; gamma-Aminobutyric Acid; Synaptic Transmission
PubMed: 37536384
DOI: 10.1016/j.nbd.2023.106248 -
Channels (Austin, Tex.) Dec 2023Voltage-gated sodium channels initiate action potentials in nerve and muscle, and voltage-gated calcium channels couple depolarization of the plasma membrane to... (Review)
Review
Voltage-gated sodium channels initiate action potentials in nerve and muscle, and voltage-gated calcium channels couple depolarization of the plasma membrane to intracellular events such as secretion, contraction, synaptic transmission, and gene expression. In this Review and Perspective article, I summarize early work that led to identification, purification, functional reconstitution, and determination of the amino acid sequence of the protein subunits of sodium and calcium channels and showed that their pore-forming subunits are closely related. Decades of study by antibody mapping, site-directed mutagenesis, and electrophysiological recording led to detailed two-dimensional structure-function maps of the amino acid residues involved in voltage-dependent activation and inactivation, ion permeation and selectivity, and pharmacological modulation. Most recently, high-resolution three-dimensional structure determination by X-ray crystallography and cryogenic electron microscopy has revealed the structural basis for sodium and calcium channel function and pharmacological modulation at the atomic level. These studies now define the chemical basis for electrical signaling and provide templates for future development of new therapeutic agents for a range of neurological and cardiovascular diseases.
Topics: Calcium Channels; Sodium; Voltage-Gated Sodium Channels; Amino Acid Sequence; Action Potentials; Calcium
PubMed: 37983307
DOI: 10.1080/19336950.2023.2281714 -
Journal of Cell Science Jul 2023Neuronal dense-core vesicles (DCVs) contain neuropeptides and much larger proteins that affect synaptic growth and plasticity. Rather than using full collapse exocytosis...
Neuronal dense-core vesicles (DCVs) contain neuropeptides and much larger proteins that affect synaptic growth and plasticity. Rather than using full collapse exocytosis that commonly mediates peptide hormone release by endocrine cells, DCVs at the Drosophila neuromuscular junction release their contents via fusion pores formed by kiss-and-run exocytosis. Here, we used fluorogen-activating protein (FAP) imaging to reveal the permeability range of synaptic DCV fusion pores and then show that this constraint is circumvented by cAMP-induced extra fusions with dilating pores that result in DCV emptying. These Ca2+-independent full fusions require PKA-R2, a PKA phosphorylation site on Complexin and the acute presynaptic function of Rugose, the homolog of mammalian neurobeachin, a PKA-R2 anchor implicated in learning and autism. Therefore, localized Ca2+-independent cAMP signaling opens dilating fusion pores to release large cargoes that cannot pass through the narrower fusion pores that mediate spontaneous and activity-dependent neuropeptide release. These results imply that the fusion pore is a variable filter that differentially sets the composition of proteins released at the synapse by independent exocytosis triggers responsible for routine peptidergic transmission (Ca2+) and synaptic development (cAMP).
Topics: Animals; Synaptic Vesicles; Calcium; Synapses; Drosophila; Drosophila Proteins; Synaptic Transmission; Neuropeptides; Exocytosis; Membrane Fusion; Mammals
PubMed: 37303204
DOI: 10.1242/jcs.261026 -
Nature Sep 2023AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca-impermeable, or...
AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca-impermeable, or GluA2-lacking and Ca-permeable. Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies, structural information for GluA2-lacking receptors is currently absent. Here we determine and characterize cryo-electron microscopy structures of the GluA1 homotetramer, fully occupied with TARPγ3 auxiliary subunits (GluA1/γ3). The gating core of both resting and open-state GluA1/γ3 closely resembles GluA2-containing receptors. However, the sequence-diverse N-terminal domains (NTDs) give rise to a highly mobile assembly, enabling domain swapping and subunit re-alignments in the ligand-binding domain tier that are pronounced in desensitized states. These transitions underlie the unique kinetic properties of GluA1. A GluA2 mutant (F231A) increasing NTD dynamics phenocopies this behaviour, and exhibits reduced synaptic responses, reflecting the anchoring function of the AMPAR NTD at the synapse. Together, this work underscores how the subunit-diverse NTDs determine subunit arrangement, gating properties and ultimately synaptic signalling efficiency among AMPAR subtypes.
Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Glutamic Acid; Cryoelectron Microscopy; Synaptic Transmission; Synapses
PubMed: 37704721
DOI: 10.1038/s41586-023-06528-0 -
ELife Aug 2023A new mechanism involving intermediate gating states of calcium channels explains how analogue postsynaptic potentials influence neurotransmitter release.
A new mechanism involving intermediate gating states of calcium channels explains how analogue postsynaptic potentials influence neurotransmitter release.
Topics: Calcium Channels; Synaptic Transmission; Calcium; Neurotransmitter Agents
PubMed: 37565652
DOI: 10.7554/eLife.90546