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The Journal of Physiology Jan 2021Fast excitatory synaptic transmission in the mammalian brain is largely mediated by AMPA-type ionotropic glutamate receptors (AMPARs), which are activated by the... (Review)
Review
Fast excitatory synaptic transmission in the mammalian brain is largely mediated by AMPA-type ionotropic glutamate receptors (AMPARs), which are activated by the neurotransmitter glutamate. In synapses, the function of AMPARs is tuned by their auxiliary subunits, a diverse set of membrane proteins associated with the core pore-forming subunits of the AMPARs. Each auxiliary subunit provides distinct functional modulation of AMPARs, ranging from regulation of trafficking to shaping ion channel gating kinetics. Understanding the molecular mechanism of the function of these complexes is key to decoding synaptic modulation and their global roles in cognitive activities, such as learning and memory. Here, we review the structural and molecular complexity of AMPAR-auxiliary subunit complexes, as well as their functional diversity in different brain regions. We suggest that the recent structural information provides new insights into the molecular mechanisms underlying synaptic functions of AMPAR-auxiliary subunit complexes.
Topics: Animals; Glutamic Acid; Ion Channel Gating; Protein Subunits; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 32004381
DOI: 10.1113/JP278701 -
Nature Nov 2023The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine...
The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumour proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity that contributes to memory and learning in the healthy brain. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.
Topics: Animals; Child; Humans; Adaptation, Physiological; Brain-Derived Neurotrophic Factor; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Proliferation; Disease Progression; Glioma; Glutamic Acid; Neuronal Plasticity; Neurons; Receptor, trkB; Receptors, AMPA; Signal Transduction; Synapses; Tumor Microenvironment; Optogenetics
PubMed: 37914930
DOI: 10.1038/s41586-023-06678-1 -
Nature Jul 2021Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into...
Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins. It is unclear whether neurexin-cerebellin-GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1-cerebellin-2 and neurexin-3-cerebellin-2 complexes differentially regulate NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-3 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5-13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin-cerebellin signals into postsynaptic receptor responses.
Topics: Amino Acid Motifs; Animals; Calcium-Binding Proteins; Cell Membrane; Excitatory Postsynaptic Potentials; Female; Glutamate Dehydrogenase; Male; Mice; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Protein Precursors; Receptors, AMPA; Receptors, Ionotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses
PubMed: 34135511
DOI: 10.1038/s41586-021-03661-6 -
Nature Communications Oct 2020Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To...
Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.
Topics: Adolescent; Adult; Biopsy; Case-Control Studies; Cell Nucleus; Datasets as Topic; Drug Resistant Epilepsy; Epilepsy, Temporal Lobe; Female; Glutamic Acid; Humans; Magnetic Resonance Imaging; Male; Microdissection; Middle Aged; Models, Genetic; Nerve Net; Neurons; RNA-Seq; Receptors, AMPA; Receptors, Glutamate; Signal Transduction; Single-Cell Analysis; Temporal Lobe; Transcription, Genetic; Transcriptome; Up-Regulation; Young Adult
PubMed: 33028830
DOI: 10.1038/s41467-020-18752-7 -
Current Opinion in Neurobiology Aug 2023Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for... (Review)
Review
Cerebellins (Cbln1-4) are secreted adaptor proteins that connect presynaptic neurexins (Nrxn1-3) to postsynaptic ligands (GluD1/2 for Cbln1-3 vs. DCC and Neogenin-1 for Cbln4). Classical studies demonstrated that neurexin-Cbln1-GluD2 complexes organize cerebellar parallel-fiber synapses, but the role of cerebellins outside of the cerebellum has only recently been clarified. In synapses of the hippocampal subiculum and prefrontal cortex, Nrxn1-Cbln2-GluD1 complexes strikingly upregulate postsynaptic NMDA-receptors, whereas Nrxn3-Cbln2-GluD1 complexes conversely downregulate postsynaptic AMPA-receptors. At perforant-path synapses in the dentate gyrus, in contrast, neurexin/Cbln4/Neogenin-1 complexes are essential for LTP without affecting basal synaptic transmission or NMDA- or AMPA-receptors. None of these signaling pathways are required for synapse formation. Thus, outside of the cerebellum neurexin/cerebellin complexes regulate synapse properties by activating specific downstream receptors.
Topics: N-Methylaspartate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Nerve Tissue Proteins; Synapses; Receptors, AMPA
PubMed: 37209532
DOI: 10.1016/j.conb.2023.102727 -
Brain : a Journal of Neurology May 2024AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or...
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants.
Topics: Humans; Male; Female; Neurodevelopmental Disorders; Child; Child, Preschool; Receptors, AMPA; Phenotype; Adolescent; Loss of Function Mutation; Gain of Function Mutation; Infant; Adult; Young Adult
PubMed: 38038360
DOI: 10.1093/brain/awad403 -
Nature Jun 2021AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and...
AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.
Topics: Allosteric Regulation; Animals; Binding Sites; Calcium Channels; Carrier Proteins; Cryoelectron Microscopy; Female; Hippocampus; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Models, Molecular; Receptors, AMPA
PubMed: 33981040
DOI: 10.1038/s41586-021-03540-0 -
The Journal of Physiology Jan 2022
Topics: Glutamic Acid; Kainic Acid; Receptors, AMPA; Receptors, Ionotropic Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate
PubMed: 35028955
DOI: 10.1113/JP282389 -
Neuropharmacology Nov 2021RNA aptamers are single-stranded RNA molecules, and they are selected against a target of interest so that they can bind to and modulate the activity of the target, such... (Review)
Review
RNA aptamers are single-stranded RNA molecules, and they are selected against a target of interest so that they can bind to and modulate the activity of the target, such as inhibiting the target activity, with high potency and selectivity. Antagonists, such as RNA aptamers, acting on AMPA receptors, a major subtype of ionotropic glutamate receptors, are potential drug candidates for treatment of a number of CNS diseases that involve excessive receptor activation and/or elevated receptor expression. Here we review the approach to discover RNA aptamers targeting AMPA receptors from a random sequence library (∼10 sequences) through a process called systematic evolution of ligands by exponential enrichment (SELEX). As compared with small-molecule compounds, RNA aptamers are a new class of regulatory agents with interesting and desirable pharmacological properties. Some AMPA receptor aptamers we have developed are presented in this review. The promises and challenges of translating RNA aptamers into potential drugs and treatment options are also discussed. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.
Topics: Animals; Aptamers, Nucleotide; Central Nervous System Diseases; Humans; Receptors, AMPA
PubMed: 34509496
DOI: 10.1016/j.neuropharm.2021.108761 -
The Journal of General Physiology Jan 2020JGP study suggests how the regulatory protein γ8 reopens AMPA receptor channels in the continued presence of glutamate.
JGP study suggests how the regulatory protein γ8 reopens AMPA receptor channels in the continued presence of glutamate.
Topics: Calcium Channels; Glutamic Acid; Nuclear Proteins; Receptors, AMPA
PubMed: 31825464
DOI: 10.1085/jgp.201912542