scholarly journals Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength

2021 ◽  
Vol 7 (34) ◽  
pp. eabf3126
Author(s):  
Austin M. Ramsey ◽  
Ai-Hui Tang ◽  
Tara A. LeGates ◽  
Xu-Zhuo Gou ◽  
Beatrice E. Carbone ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Synaptic Strength ◽  
Synaptic Function ◽  
The Novel ◽  
Novel Concept ◽  
The Brain

Recent evidence suggests that nano-organization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this hypothesis. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors (AMPARs), we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale declustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function and support the novel concept that adhesion molecules acutely position receptors to dynamically control synaptic strength.

scholarly journals Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength

2021 ◽  
Author(s):  
A.M. Ramsey ◽  
A.H. Tang ◽  
T.A. LeGates ◽  
X.Z. Gou ◽  
B.E. Carbone ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Synaptic Strength ◽  
Synaptic Function ◽  
The Novel ◽  
Novel Concept ◽  
The Brain

AbstractRecent evidence suggests that nanoorganization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this idea. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown. Reasoning that transcellular interactions could position AMPA receptors, we targeted a key transsynaptic adhesion molecule implicated in controlling AMPAR number, LRRTM2, using engineered, rapid proteolysis. Severing the LRRTM2 extracellular domain led quickly to nanoscale de-clustering of AMPARs away from release sites, not prompting their escape from synapses until much later. This rapid remodeling of AMPAR position produced significant deficits in evoked, but not spontaneous, postsynaptic receptor activation. These results dissociate receptor numbers from their nanopositioning in determination of synaptic function, and support the novel concept that adhesion molecules acutely position AMPA receptors to dynamically control synaptic strength.

scholarly journals Phylogenetic Core Groups: a promising concept in search of a consistent methodological framework

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alberto Pascual-García
Keyword(s):  
Microbial Communities ◽  
Microbial Ecology ◽  
Environmental Conditions ◽  
The Novel ◽  
Methodological Framework ◽  
Operational Taxonomic Units ◽  
Traditional Classification ◽  
Taxonomical Classification ◽  
Novel Concept

AbstractIn this comment, we analyse the conceptual framework proposed by Aguirre de Cárcer (Microbiome 7:142, 2019), introducing the novel concept of Phylogenetic Core Groups (PCGs). This notion aims to complement the traditional classification in operational taxonomic units (OTUs), widely used in microbial ecology, to provide a more intrinsic taxonomical classification which avoids the use of pre-determined thresholds. However, to introduce this concept, the author frames his proposal in a wider theoretical framework based on a conceptualization of selection that we argue is a tautology. This blurs the subsequent formulation of an assembly principle for microbial communities, favouring that some contradictory examples introduced to support the framework appear aligned in their conclusions. And more importantly, under this framework and its derived methodology, it is not possible to infer PCGs from data in a consistent way. We reanalyse the proposal to identify its logical and methodological flaws and, through the analysis of synthetic scenarios, we propose a number of methodological refinements to contribute towards the determination of PCGs in a consistent way. We hope our analysis will promote the exploration of PCGs as a potentially valuable tool, helping to bridge the gap between environmental conditions and community composition in microbial ecology.

scholarly journals Expression mechanisms underlying long-term potentiation: a postsynaptic view

2003 ◽  
Vol 358 (1432) ◽  
pp. 721-726 ◽  
Author(s):  
Roger A. Nicoll
Keyword(s):  
Nmda Receptor ◽  
Ampa Receptors ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Covalent Modification ◽  
Term Potentiation ◽  
Expression Mechanism

This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particular N -methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.

scholarly journals Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking

2020 ◽  
Vol 219 (10) ◽  
Author(s):  
Maria Casas ◽  
Rut Fadó ◽  
José Luis Domínguez ◽  
Aina Roig ◽  
Moena Kaku ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Cortical Neurons ◽  
Metabolic Stress ◽  
Phosphatidyl Inositol ◽  
Synaptic Function ◽  
Glucose Depletion ◽  
Malonyl Coa ◽  
Dependent Inhibition ◽  
Excitatory Neurotransmission ◽  
The Brain

Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1. In normal conditions, CPT1C down-regulates SAC1 catalytic activity, allowing efficient GluA1 trafficking to the plasma membrane. However, under low malonyl-CoA levels, such as during glucose depletion, CPT1C-dependent inhibition of SAC1 is released, facilitating SAC1’s translocation to ER-TGN contact sites to decrease TGN PI(4)P pools and trigger GluA1 retention at the TGN. Results reveal that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and provide the first report of a SAC1 inhibitor. Moreover, they shed light on how nutrients can affect synaptic function and cognition.

scholarly journals α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

2016 ◽  
Vol 113 (19) ◽  
pp. E2695-E2704 ◽  
Author(s):  
Mengping Wei ◽  
Jian Zhang ◽  
Moye Jia ◽  
Chaojuan Yang ◽  
Yunlong Pan ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Surface Expression ◽  
Inhibitory Effect ◽  
Synaptic Function ◽  
Excitatory Synapses ◽  
C Terminus ◽  
Ampar Trafficking ◽  
Excitatory Neurotransmission ◽  
Induced Currents ◽  
The Brain

In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.

Physiological roles of spine motility: development, plasticity and disorders

2005 ◽  
Vol 33 (6) ◽  
pp. 1299-1302 ◽  
Author(s):  
R.A. McKinney
Keyword(s):  
Dendritic Spines ◽  
Fluorescent Protein ◽  
Glutamate Release ◽  
Physiological Role ◽  
Receptor Activation ◽  
Synaptic Function ◽  
Dynamic Interactions ◽  
Excitatory Neurotransmitter ◽  
Green Fluorescent

The vast majority of excitatory connections in the hippocampus are made on dendritic spines. Both dendritic spines and molecules within the membrane are able to move, but the physiological role of these movements is unclear. In the developing brain, spines show highly dynamic behaviour thought to facilitate new synaptic connections. Dynamic movements also occur in adults but the role of this movement is unclear. We have studied the effects of the most important excitatory neurotransmitter, glutamat, and found receptor activation to enhance movement of molecules within the spine membrane. This action of glutamate may be important in regulating the trafficking of neurotransmitter receptors that mediate change in synaptic function. In addition, we have studied the dynamic interactions between pre- and postsynaptic structures labelled with FM 4-64 and a membrane-targeted GFP (green fluorescent protein), respectively, in hippocampal slice cultures under conditions of increased activity, such as epilepsy. Our findings suggest a novel form of activity-dependent synaptic plasticity where spontaneous glutamate release is sufficient to trigger changes in the hippocampal microcircuitry by attracting neighbouring spines responsive to an enhanced level of extracellular glutamate.

scholarly journals Integrated information structure collapses with anesthetic loss of conscious arousal in Drosophila melanogaster

2021 ◽  
Vol 17 (2) ◽  
pp. e1008722
Author(s):  
Angus Leung ◽  
Dror Cohen ◽  
Bruno van Swinderen ◽  
Naotsugu Tsuchiya
Keyword(s):  
Information Structure ◽  
Conscious Experience ◽  
The Novel ◽  
Information Structures ◽  
Specific Content ◽  
Level Of Consciousness ◽  
Rich Information ◽  
Novel Concept ◽  
The Brain ◽  
Integrated Information

The physical basis of consciousness remains one of the most elusive concepts in current science. One influential conjecture is that consciousness is to do with some form of causality, measurable through information. The integrated information theory of consciousness (IIT) proposes that conscious experience, filled with rich and specific content, corresponds directly to a hierarchically organised, irreducible pattern of causal interactions; i.e. an integrated informational structure among elements of a system. Here, we tested this conjecture in a simple biological system (fruit flies), estimating the information structure of the system during wakefulness and general anesthesia. Consistent with this conjecture, we found that integrated interactions among populations of neurons during wakefulness collapsed to isolated clusters of interactions during anesthesia. We used classification analysis to quantify the accuracy of discrimination between wakeful and anesthetised states, and found that informational structures inferred conscious states with greater accuracy than a scalar summary of the structure, a measure which is generally championed as the main measure of IIT. In stark contrast to a view which assumes feedforward architecture for insect brains, especially fly visual systems, we found rich information structures, which cannot arise from purely feedforward systems, occurred across the fly brain. Further, these information structures collapsed uniformly across the brain during anesthesia. Our results speak to the potential utility of the novel concept of an “informational structure” as a measure for level of consciousness, above and beyond simple scalar values.

scholarly journals Properties of individual hippocampal synapses influencing NMDA-receptor activation by spontaneous neurotransmission

2019 ◽  
Author(s):  
Sarah R. Metzbower ◽  
Yuyoung Joo ◽  
David R. Benavides ◽  
Thomas A. Blanpied
Keyword(s):  
Nmda Receptor ◽  
Glutamate Release ◽  
Critical Role ◽  
Dendritic Tree ◽  
Receptor Activation ◽  
Synaptic Function ◽  
Spontaneous Release ◽  
Synaptic Development ◽  
Nmdar Activation ◽  
Spontaneous Activation

AbstractNMDA receptor (NMDAR) activation is critical for maintenance and modification of synapse strength. Specifically, NMDAR activation by spontaneous glutamate release has been shown to mediate forms of synaptic plasticity as well as synaptic development. Interestingly, there is evidence that within individual synapses each release mode may be segregated such that postsynaptically there are distinct pools of responsive receptors. In order to examine potential regulators of NMDAR activation due to spontaneous glutamate release in cultured rat hippocampal neurons, we utilized GCaMP6f imaging at single synapses in concert with confocal and super-resolution imaging. Using these single spine approaches, we found that Ca2+entry activated by spontaneous release tends to be carried by GluN2B-NMDARs. Additionally, the amount of NMDAR activation varies greatly both between synapses and within synapses, and is unrelated to spine and synapse size, but does correlate loosely with synapse distance from the soma. Despite the critical role of spontaneous activation of NMDARs in maintaining synaptic function, their activation seems to be controlled factors other than synapse size or synapse distance from the soma. It is most likely that NMDAR activation by spontaneous release influenced variability in subsynaptic receptor position, release site position, vesicle content, and channel properties. Therefore, spontaneous activation of NMDARs appears to be regulated distinctly from other receptor types, notably AMPARs, within individual synapses.Significance StatementUnderstanding the underlying synaptic mechanisms for learning and memory is critically important to the field of neuroscience and for human health. A key neurotransmitter receptor type involved in learning is the NMDA receptor, and exploration of its regulation is vital. In this study, we optimized optical tools to allow detailed characterization of NMDA receptor activity at single synapses, along with analysis of structural features of the imaged synapses. The amount of receptor activation is independent of the size of the synapse, but weakly dependent on synapse position within the dendritic tree. Notably, we found that NMDA receptors activated following spontaneous neurotransmitter release tend be GluN2B-containing receptors. Thus, the unique mechanisms that regulate the number and positioning of these receptors within synapses will have important consequences for control of synaptic development and signaling.

scholarly journals isiKnock: in silico knockouts in biochemical pathways

2018 ◽  
Author(s):  
Jennifer Scheidel ◽  
Heiko Giese ◽  
Börje Schweizer ◽  
Leonie Amstein ◽  
Jörg Ackermann ◽  
...  
Keyword(s):  
Steady State ◽  
Mathematical Models ◽  
Open Source ◽  
Cell Response ◽  
In Silico ◽  
Receptor Activation ◽  
The Novel ◽  
Biochemical Pathways ◽  
Novel Concept ◽  
Microsoft Windows

AbstractSummaryisiKnock is a new software that automatically conducts in silico knockouts for mathematical models of biochemical pathways. The software allows for the prediction of the behavior of biological systems after single or multiple knockout. The implemented algorithm applies transition invariants and the novel concept of Manatee invariants. A knockout matrix visualizes the results. The tool enables the analysis of dependencies, for example, in signal flows from the receptor activation to the cell response at steady state.Availability and ImplementationisiKnock is an open-source tool, freely available at http://www.bioinformatik.uni-frankfurt.de/tools/isiKnock/index.php. It requires at least Java 8 and runs under Microsoft Windows, Linux, and Mac [email protected]

scholarly journals Reactive Astrocytosis in a Mouse Model of Chronic Polyamine Catabolism Activation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1274
Author(s):  
Chiara Cervetto ◽  
Monica Averna ◽  
Laura Vergani ◽  
Marco Pedrazzi ◽  
Sarah Amato ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Catalase Activity ◽  
Calcium Influx ◽  
Receptor Activation ◽  
Spermine Oxidase ◽  
Polyamine Catabolism ◽  
Chronic Activation ◽  
The Brain ◽  
Neuron Injury ◽  
Increased Susceptibility

Background: In the brain, polyamines are mainly synthesized in neurons, but preferentially accumulated in astrocytes, and are proposed to be involved in neurodegenerative/neuroinflammatory disorders and neuron injury. A transgenic mouse overexpressing spermine oxidase (SMOX, which specifically oxidizes spermine) in the neocortex neurons (Dach-SMOX mouse) was proved to be a model of increased susceptibility to excitotoxic injury. Methods: To investigate possible alterations in synapse functioning in Dach-SMOX mouse, both cerebrocortical nerve terminals (synaptosomes) and astrocytic processes (gliosomes) were analysed by assessing polyamine levels, ezrin and vimentin content, glutamate AMPA receptor activation, calcium influx, and catalase activity. Results: The main findings are as follows: (i) the presence of functional calcium-permeable AMPA receptors in synaptosomes from both control and Dach-SMOX mice, and in gliosomes from Dach-SMOX mice only; (ii) reduced content of spermine in gliosomes from Dach-SMOX mice; and (iii) down-regulation and up-regulation of catalase activity in synaptosomes and gliosomes, respectively, from Dach-SMOX mice. Conclusions: Chronic activation of SMOX in neurons leads to major changes in the astrocyte processes including reduced spermine levels, increased calcium influx through calcium-permeable AMPA receptors, and stimulation of catalase activity. Astrocytosis and the astrocyte process alterations, depending on chronic activation of polyamine catabolism, result in synapse dysregulation and neuronal suffering.

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