scholarly journals Molecular Mechanisms of Neurotransmitter Release Control Distinct Features of Sensory Coding Reliability

2021 ◽  
Author(s):  
Eyal Rozenfeld ◽  
Nadine Ehmann ◽  
Julia E. Manoim ◽  
Robert J. Kittel ◽  
Moshe Parnas
Keyword(s):  
Neurotransmitter Release ◽  
Action Potentials ◽  
Neural Coding ◽  
Information Transfer ◽  
Molecular Mechanisms ◽  
Neural Code ◽  
Temporal Coding ◽  
Neural Representation ◽  
Major Mechanism

AbstractA key requirement for the repeated identification of a stimulus is a reliable neural representation each time it is encountered. Neural coding is often considered to rely on two major coding schemes: the firing rate of action potentials, known as rate coding, and the precise timing of action potentials, known as temporal coding. Synaptic transmission is the major mechanism of information transfer between neurons. While theoretical studies have examined the effects of neurotransmitter release probability on neural code reliability, it has not yet been addressed how different components of the release machinery affect coding of physiological stimuli in vivo. Here, we use the first synapse of the Drosophila olfactory system to show that the reliability of the neural code is sensitive to perturbations of specific presynaptic proteins controlling distinct stages of neurotransmitter release. Notably, the presynaptic manipulations decreased coding reliability of postsynaptic neurons only at high odor intensity. We further show that while the reduced temporal code reliability arises from monosynaptic effects, the reduced rate code reliability arises from circuit effects, which include the recruitment of inhibitory local neurons. Finally, we find that reducing neural coding reliability decreases behavioral reliability of olfactory stimulus classification.

scholarly journals Temporally precise control of single-neuron spiking by juxtacellular nanostimulation

2017 ◽  
Vol 117 (3) ◽  
pp. 1363-1378 ◽  
Author(s):  
Maik C. Stüttgen ◽  
Lourens J. P. Nonkes ◽  
H. Rüdiger A. P. Geis ◽  
Paul H. Tiesinga ◽  
Arthur R. Houweling
Keyword(s):  
Short Duration ◽  
Cortical Neurons ◽  
Action Potentials ◽  
Neural Coding ◽  
Spike Trains ◽  
Precise Control ◽  
Neuronal Spike Trains ◽  
The Impact ◽  
Activity Dependent

Temporal patterns of action potentials influence a variety of activity-dependent intra- and intercellular processes and play an important role in theories of neural coding. Elucidating the mechanisms underlying these phenomena requires imposing spike trains with precisely defined patterns, but this has been challenging due to the limitations of existing stimulation techniques. Here we present a new nanostimulation method providing control over the action potential output of individual cortical neurons. Spikes are elicited through the juxtacellular application of short-duration fluctuating currents (“kurzpulses”), allowing for the sub-millisecond precise and reproducible induction of arbitrary patterns of action potentials at all physiologically relevant firing frequencies (<120 Hz), including minute-long spike trains recorded in freely moving animals. We systematically compared our method to whole cell current injection, as well as optogenetic stimulation, and show that nanostimulation performance compares favorably with these techniques. This new nanostimulation approach is easily applied, can be readily performed in awake behaving animals, and thus promises to be a powerful tool for systematic investigations into the temporal elements of neural codes, as well as the mechanisms underlying a wide variety of activity-dependent cellular processes. NEW & NOTEWORTHY Assessing the impact of temporal features of neuronal spike trains requires imposing arbitrary patterns of spiking on individual neurons during behavior, but this has been difficult to achieve due to limitations of existing stimulation methods. We present a technique that overcomes these limitations by using carefully designed short-duration fluctuating juxtacellular current injections, which allow for the precise and reliable evocation of arbitrary patterns of neuronal spikes in single neurons in vivo.

scholarly journals Single calcium channel nanodomains drive presynaptic calcium entry at lamprey reticulospinal presynaptic terminals

2021 ◽  
Author(s):  
S Ramachandran ◽  
S Rodgriguez ◽  
M Potcoava ◽  
S Alford
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Action Potentials ◽  
Information Transfer ◽  
Single Channel ◽  
Light Sheet ◽  
Stochastic Variation ◽  
Presynaptic Terminals ◽  
Light Sheet Microscopy ◽  
Presynaptic Calcium

AbstractSynchronous neurotransmission is central to efficient information transfer in neural circuits, requiring precise coupling between action potentials, Ca2+ entry and neurotransmitter release. However, determinations of Ca2+ requirements for release, which may originate from entry through single voltage-gated Ca2+ channels, remain largely unexplored in simple active zone synapses common in the nervous system. Understanding these requirements is key to addressing Ca2+ channel and synaptic dysfunction underlying numerous neurological and neuropsychiatric disorders. Here, we present single channel analysis of evoked active zone Ca2+ entry, using cell-attached patch clamp and lattice light sheet microscopy over active zones at single central lamprey reticulospinal presynaptic terminals. Our findings show a small pool (mean of 23) of Ca2+ channels at each terminal, comprising subtypes N-type (CaV2.2), P/Q-type (CaV2.1) and R-type (CaV2.3), available to gate neurotransmitter release. Significantly, of this pool only 1-6 (mean of 4) channels open upon depolarization. High temporal fidelity lattice light sheet imaging reveals AP-evoked Ca2+ transients exhibiting quantal amplitude variations between action potentials and stochastic variation of precise locations of Ca2+ entry within the active zone. Further, Ca2+ channel numbers at each active zone correlate to the number of presynaptic primed synaptic vesicles. Together, our findings indicate 1:1 association of Ca2+ channels with primed vesicles, suggesting Ca2+ entry via as few as one channel may trigger neurotransmitter release.

scholarly journals Bassoon controls synaptic vesicle pools via regulation of presynaptic phosphorylation and cAMP homeostasis

2021 ◽  
Author(s):  
Carolina Montenegro-Venegas ◽  
Debarpan Guhathakurta ◽  
Eneko Pina-Fernandez ◽  
Maria Andres-Alonso ◽  
Florian Plattner ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Molecular Mechanisms ◽  
Cultured Neurons ◽  
Glutamatergic Synapses ◽  
Vesicle Pools ◽  
Downstream Effectors ◽  
Synapsin 1

Neuronal presynaptic terminals contain hundreds of neurotransmitter-filled synaptic vesicles (SVs). The morphologically uniform SVs differ in their release competence segregating into functional pools that differentially contribute to neurotransmission. The presynaptic scaffold bassoon is required for neurotransmission, but the underlying molecular mechanisms are unknown. We report that glutamatergic synapses lacking bassoon featured a decreased SV release competence and increased resting pool of SV as observed by imaging of SV release in cultured neurons. Further analyses in vitro and in vivo revealed a dysregulation of CDK5/calcineurin and cAMP/PKA presynaptic signalling resulting in an aberrant phosphorylation of their downstream effectors synapsin 1 and SNAP25, which are well-known regulators of SV release competence. An acute pharmacological restoration of physiological CDK5 and cAMP/PKA activity fully normalised the SV pools in neurons lacking bassoon. Finally, we demonstrated that CDK5-dependent regulation of PDE4 activity controls SV release competence by interaction with cAMP/PKA signalling. These data reveal that bassoon organises SV pools via regulation of presynaptic phosphorylation and indicate an involvement of PDE4 in the control of neurotransmitter release.

scholarly journals Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Gabby Rudenko
Keyword(s):  
Information Transfer ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Scale Up ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Protein Partners

Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, forming trans-complexes spanning the synaptic cleft or cis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

scholarly journals Lactobacillus acidophilus upregulates intestinal NHE3 expression and function

2012 ◽  
Vol 303 (12) ◽  
pp. G1393-G1401 ◽  
Author(s):  
Varsha Singh ◽  
Geetu Raheja ◽  
Alip Borthakur ◽  
Anoop Kumar ◽  
Ravinder K. Gill ◽  
...  
Keyword(s):  
Lactobacillus Acidophilus ◽  
Molecular Mechanisms ◽  
Major Mechanism ◽  
Protein Levels ◽  
Nacl Absorption ◽  
Human Colonic Adenocarcinoma Cell ◽  
And Function ◽  
Exchange Activity

A major mechanism of electroneutral NaCl absorption in the human ileum and colon involves coupling of Na+/H+ and Cl−/HCO3− exchangers. Disturbances in these mechanisms have been implicated in diarrheal conditions. Probiotics such as Lactobacillus have been indicated to be beneficial in the management of gastrointestinal disorders, including diarrhea. However, the molecular mechanisms underlying antidiarrheal effects of probiotics have not been fully understood. We have previously demonstrated Lactobacillus acidophilus (LA) to stimulate Cl−/HCO3− exchange activity via an increase in the surface levels and expression of the Cl−/HCO3− exchanger DRA in vitro and in vivo. However, the effects of LA on NHE3, the Na+/H+ exchanger involved in the coupled electroneutral NaCl absorption, are not known. Current studies were, therefore, undertaken to investigate the effects of LA on the function and expression of NHE3 and to determine the mechanisms involved. Treatment of Caco2 cells with LA or its conditioned culture supernatant (CS) for 8–24 h resulted in a significant increase in Na+/H+ exchange activity, mRNA, and protein levels of NHE3. LA-CS upregulation of NHE3 function and expression was also observed in SK-CO15 cells, a human colonic adenocarcinoma cell line. Additionally, LA treatment increased NHE3 promoter activity, suggesting involvement of transcriptional mechanisms. In vivo, mice gavaged with live LA showed significant increase in NHE3 mRNA and protein expression in the ileum and colonic regions. In conclusion, LA-induced increase in NHE3 expression may contribute to the upregulation of intestinal electrolyte absorption and might underlie the potential antidiarrheal effects of probiotics.

scholarly journals Alterations of action potentials and the localization of Nav1.6 sodium channels in spared axons after hemisection injury of the spinal cord in adult rats

2011 ◽  
Vol 105 (3) ◽  
pp. 1033-1044 ◽  
Author(s):  
Arsen S. Hunanyan ◽  
Valentina Alessi ◽  
Samik Patel ◽  
Damien D. Pearse ◽  
Gary Matthews ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sodium Channels ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Input Resistance ◽  
Ultrastructural Changes ◽  
Resting Membrane Potential ◽  
Adult Rats ◽  
Cord Injury

Previously, we reported a pronounced reduction in transmission through surviving axons contralateral to chronic hemisection (HX) of adult rat spinal cord. To examine the cellular and molecular mechanisms responsible for this diminished transmission, we recorded intracellularly from lumbar lateral white matter axons in deeply anesthetized adult rats in vivo and measured the propagation of action potentials (APs) through rubrospinal/reticulospinal tract (RST/RtST) axons contralateral to chronic HX at T10. We found decreased excitability in these axons, manifested by an increased rheobase to trigger APs and longer latency for AP propagation passing the injury level, without significant differences in axonal resting membrane potential and input resistance. These electrophysiological changes were associated with altered spatial localization of Nav1.6 sodium channels along axons: a subset of axons contralateral to the injury exhibited a diffuse localization (>10 μm spread) of Nav1.6 channels, a pattern characteristic of demyelinated axons (Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Proc Natl Acad Sci USA 101: 8168–8173, 2004b). This result was substantiated by ultrastructural changes seen with electron microscopy, in which an increased number of large-caliber, demyelinated RST axons were found contralateral to the chronic HX. Therefore, an increased rheobase, pathological changes in the distribution of Nav1.6 sodium channels, and the demyelination of contralateral RST axons are likely responsible for their decreased conduction chronically after HX and thus may provide novel targets for strategies to improve function following incomplete spinal cord injury.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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