Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding DOI
Jan‐Marino Ramirez, Nicholas Burgraff, Aguan Wei

et al.

Journal of Neurophysiology, Journal Year: 2021, Volume and Issue: 125(5), P. 1899 - 1919

Published: April 7, 2021

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within United States, rate from abuse since early 1990s has grown disproportionally, prompting classification as a nationwide “epidemic.” Since this time, we have begun to unravel many fundamental cellular systems-level mechanisms opioid-related death. However, factors such individual vulnerability, neuromodulatory compensation, redundancy effects across central peripheral nervous systems created barrier concise, integrative view OIRD. review, bring together multiple perspectives in field OIRD create an overarching viewpoint what know, where essential topic research going forward into future.

Language: Английский

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels DOI Open Access
Kasper B. Hansen, Lonnie P. Wollmuth, Derek Bowie

et al.

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(4), P. 1469 - 1658

Published: Oct. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Language: Английский

Citations

459
Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future DOI Creative Commons
Yun Zhang, Huaqiu Chen, Ran Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Language: Английский

Citations

380
CaM Kinase: Still Inspiring at 40 DOI Creative Commons
K. Ulrich Bayer, Howard Schulman

Neuron, Journal Year: 2019, Volume and Issue: 103(3), P. 380 - 394

Published: Aug. 1, 2019

Language: Английский

Citations

290
Neuromodulation of Spike-Timing-Dependent Plasticity: Past, Present, and Future DOI Creative Commons
Zuzanna Brzosko, Susanna B. Mierau, Ole Paulsen

et al.

Neuron, Journal Year: 2019, Volume and Issue: 103(4), P. 563 - 581

Published: Aug. 1, 2019

Language: Английский

Citations

201
Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM DOI Open Access
Yan Zhao, Shanshuang Chen, Adam Swensen

et al.

Science, Journal Year: 2019, Volume and Issue: 364(6438), P. 355 - 362

Published: April 11, 2019

Glutamate-gated AMPA receptors mediate the fast component of excitatory signal transduction at chemical synapses throughout all regions mammalian brain. are tetrameric assemblies composed four subunits, GluA1-GluA4. Despite decades study, subunit composition, arrangement, and molecular structure native remain unknown. Here we elucidate structures 10 distinct receptor complexes by single-particle cryo-electron microscopy (cryo-EM). We find that subunits arranged nonstochastically, with GluA2 preferentially occupying B D positions tetramer triheteromeric comprising a major population receptors. Cryo-EM maps define for S2-M4 linkers between ligand-binding transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.

Language: Английский

Citations

172
Twenty Years of SynGAP Research: From Synapses to Cognition DOI Creative Commons
Timothy R. Gamache, Yoichi Araki, Richard L. Huganir

et al.

Journal of Neuroscience, Journal Year: 2020, Volume and Issue: 40(8), P. 1596 - 1605

Published: Feb. 19, 2020

SynGAP is a potent regulator of biochemical signaling in neurons and plays critical roles neuronal function. It was first identified 1998, has since been extensively characterized as mediator synaptic plasticity. Because its involvement plasticity, emerged protein for normal cognitive In recent years, mutations the SYNGAP1 gene have shown to cause intellectual disability humans linked other neurodevelopmental disorders, such autism spectrum disorders schizophrenia. While structure function well characterized, unified understanding various at synapse contributions remains be achieved. this review, we summarize discuss current multifactorial role regulating gathered over last two decades.

Language: Английский

Citations

142
Mechanisms of ketamine and its metabolites as antidepressants DOI
Evan Hess, Lace M. Riggs, Michael Michaelides

et al.

Biochemical Pharmacology, Journal Year: 2021, Volume and Issue: 197, P. 114892 - 114892

Published: Dec. 27, 2021

Language: Английский

Citations

117
Amygdala-hippocampal innervation modulates stress-induced depressive-like behaviors through AMPA receptors DOI
Hui Ma, Chenyang Li, Jinpeng Wang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(6)

Published: Feb. 1, 2021

Significance Basal lateral amygdala and ventral CA1 are critical sites during chronic stress-induced depression. Here we demonstrated that AMPARs mediated weakening of pBLA-vCA1 innervation in mice subjected to CUMS. Stimulation via chemogenetics or administration cannabidiol (CBD) could reverse synaptosomal AMPAR decrease alleviate CUMS-induced depressive-like behaviors. These findings highlighted the importance an animal model depression revealed potential for CBD major treatment.

Language: Английский

Citations

107
Glioma synapses recruit mechanisms of adaptive plasticity DOI Creative Commons
Kathryn R. Taylor, Tara Barron,

Alexa Hui

et al.

Nature, Journal Year: 2023, Volume and Issue: 623(7986), P. 366 - 374

Published: Nov. 1, 2023

Abstract The role of the nervous system in regulation cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor 1–3 (BDNF), also electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors 4,5 . consequent glioma cell membrane depolarization proliferation 4,6 healthy brain, activity-regulated secretion BDNF promotes adaptive plasticity synaptic connectivity 7,8 strength 9–15 Here we show that malignant exhibit similar regulated BDNF. Signalling receptor tropomyosin-related kinase B 16 (TrkB) to CAMKII, trafficking membrane, resulting increased amplitude glutamate-evoked currents cells. Linking growth, graded optogenetic control potential demonstrates greater depolarizing current proliferation. This potentiation shares mechanistic features with 17–22 contributes memory learning brain 23–26 BDNF–TrkB regulates number synapses. Abrogation from microenvironment or loss TrkB expression robustly inhibits progression. Blocking genetically pharmacologically abrogates these effects on substantially prolongs survival xenograft models paediatric glioblastoma diffuse intrinsic pontine glioma. Together, findings indicate augments

Language: Английский

Citations

100
Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity DOI Creative Commons
Nagendran Ramalingam,

Shan‐Xue Jin,

Tim E. Moors

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Jan. 16, 2023

Abstract In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker pathology. However, physiological role for pS129 has remained undefined. Here we use multiple approaches to show first time that functions as regulator neuronal activity. Neuronal activity triggers sustained increase in cultured neurons (200% within 4 h). accord, brain elevated environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent phosphorylation S129-specific, reversible, confers no cytotoxicity, accumulates synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with model which stimulation enhances Plk2 kinase via calcium/calcineurin pathway counteract PP2A phosphatase efficient membrane-bound α-synuclein. Patch clamping rat SNCA −/− expressing exogenous wild-type or phospho-incompetent (S129A) suggests fine-tunes balance between excitatory inhibitory currents. Consistently, novel S129A knock-in (S129A KI ) exhibit impaired hippocampal plasticity. The discovery key function implications understanding neurotransmission adds nuance interpretation synucleinopathy biomarker.

Language: Английский

Citations

72