scholarly journals Conditioning by Subthreshold Synaptic Input Changes the Intrinsic Firing Pattern of CA3 Hippocampal Neurons

2017 ◽  
Author(s):  
Saray Soldado-Magraner ◽  
Federico Brandalise ◽  
Suraj Honnuraiah ◽  
Michael Pfeiffer ◽  
Urs Gerber ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Firing Pattern ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Spike Timing ◽  
Firing Patterns ◽  
Subthreshold Activity ◽  
Ca3 Neurons ◽  
Intrinsic Firing

AbstractUnlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike-timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions towards adapting and intrinsic burst behaviours, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade, and found that the observed transitions are likely due to recruitment of calcium and M-type potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits.New & NoteworthyDespite being widely conserved across the animal phyla, it is still a mystery why nerve cells present diverse discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit. This result implies that CA3 neurons collectively adjust their network processing to the temporal statistics of their circuit.

scholarly journals Conditioning by subthreshold synaptic input changes the intrinsic firing pattern of CA3 hippocampal neurons

2020 ◽  
Vol 123 (1) ◽  
pp. 90-106 ◽  
Author(s):  
Saray Soldado-Magraner ◽  
Federico Brandalise ◽  
Suraj Honnuraiah ◽  
Michael Pfeiffer ◽  
Marie Moulinier ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Firing Pattern ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Low Voltage ◽  
Spike Timing ◽  
Firing Patterns ◽  
Subthreshold Activity ◽  
Ca3 Neurons ◽  
Intrinsic Firing

Unlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions toward adapting and intrinsic burst behaviors, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade and found that the observed transitions are likely due to recruitment of low-voltage calcium and Kv7 potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits. NEW & NOTEWORTHY Although firing patterns are widely conserved across the animal phyla, it is still a mystery why nerve cells present such diversity of discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit, potentially adjusting their network processing to the temporal statistics of their circuit.

scholarly journals Ion Channels Set Spike Timing Regularity of Mammalian Vestibular Afferent Neurons

2010 ◽  
Vol 104 (4) ◽  
pp. 2034-2051 ◽  
Author(s):  
Radha Kalluri ◽  
Jingbing Xue ◽  
Ruth Anne Eatock
Keyword(s):  
Ion Channels ◽  
Firing Pattern ◽  
Low Voltage ◽  
Spike Timing ◽  
Resting Potential ◽  
Firing Patterns ◽  
Different Temperatures ◽  
The Difference ◽  
Current Steps ◽  
Whole Cell Recordings

In the mammalian vestibular nerve, some afferents have highly irregular interspike intervals and others have highly regular intervals. To investigate whether spike timing is determined by the afferents' ion channels, we studied spiking activity in their cell bodies, isolated from the vestibular ganglia of young rats. Whole cell recordings were made with the perforated-patch method. As previously reported, depolarizing current steps revealed distinct firing patterns. Transient neurons fired one or two onset spikes, independent of current level. Sustained neurons were more heterogeneous, firing either trains of spikes or a spike followed by large voltage oscillations. We show that the firing pattern categories are robust, occurring at different temperatures and ages, both in mice and in rats. A difference in average resting potential did not cause the difference in firing patterns, but contributed to differences in afterhyperpolarizations. A low-voltage-activated potassium current ( ILV) was previously implicated in the transient firing pattern. We show that ILV grew from the first to second postnatal week and by the second week comprised Kv1 and Kv7 (KCNQ) components. Blocking ILV converted step-evoked firing patterns from transient to sustained. Separated from their normal synaptic inputs, the neurons did not spike spontaneously. To test whether the firing-pattern categories might correspond to afferent populations of different regularity, we injected simulated excitatory postsynaptic currents at pseudorandom intervals. Sustained neurons responded to a given pattern of input with more regular firing than did transient neurons. Pharmacological block of ILV made firing more regular. Thus ion channel differences that produce transient and sustained firing patterns in response to depolarizing current steps can also produce irregular and regular spike timing.

scholarly journals FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children

2021 ◽  
Author(s):  
Thomas B Knudsen ◽  
Suzanne Compton Fitzpatrick ◽  
K Nadira De Abrew ◽  
Linda S Birnbaum ◽  
Anne Chappelle ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Healthy Children ◽  
Chemical Toxicity ◽  
Predictive Toxicology ◽  
Biological Organization ◽  
Adverse Pregnancy

Abstract FutureTox IV, a Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (USEPA, 2018). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (e.g., preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (e.g., neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.

scholarly journals Synaptic Scaling Stabilizes Persistent Activity Driven by Asynchronous Neurotransmitter Release

2011 ◽  
Vol 23 (4) ◽  
pp. 927-957 ◽  
Author(s):  
Vladislav Volman ◽  
Richard C. Gerkin
Keyword(s):  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Computational Models ◽  
Essential Feature ◽  
Network Activity ◽  
Synaptic Connectivity ◽  
The Stability ◽  
Synaptic Drive

Small networks of cultured hippocampal neurons respond to transient stimulation with rhythmic network activity (reverberation) that persists for several seconds, constituting an in vitro model of synchrony, working memory, and seizure. This mode of activity has been shown theoretically and experimentally to depend on asynchronous neurotransmitter release (an essential feature of the developing hippocampus) and is supported by a variety of developing neuronal networks despite variability in the size of populations (10–200 neurons) and in patterns of synaptic connectivity. It has previously been reported in computational models that “small-world” connection topology is ideal for the propagation of similar modes of network activity, although this has been shown only for neurons utilizing synchronous (phasic) synaptic transmission. We investigated how topological constraints on synaptic connectivity could shape the stability of reverberations in small networks that also use asynchronous synaptic transmission. We found that reverberation duration in such networks was resistant to changes in topology and scaled poorly with network size. However, normalization of synaptic drive, by reducing the variance of synaptic input across neurons, stabilized reverberation in such networks. Our results thus suggest that the stability of both normal and pathological states in developing networks might be shaped by variance-normalizing constraints on synaptic drive. We offer an experimental prediction for the consequences of such regulation on the behavior of small networks.

Laminar distribution of neuronal membrane properties in neocortex of normal and reeler mouse

1991 ◽  
Vol 66 (6) ◽  
pp. 2034-2040 ◽  
Author(s):  
L. R. Silva ◽  
M. J. Gutnick ◽  
B. W. Connors
Keyword(s):  
Cortical Neurons ◽  
Normal Mouse ◽  
Membrane Properties ◽  
Recessive Mutation ◽  
Neuronal Membrane ◽  
Firing Patterns ◽  
Postsynaptic Potentials ◽  
Intrinsic Firing ◽  
Synaptic Responses

1. Reeler is an autosomal recessive mutation of mice that alters neuronal migration during development, yielding a general inversion of the laminae in the neocortex. We recorded in vitro from slices of normal and reeler neocortex to study the influence of neuron position and shape on membrane properties and synaptic responses. 2. The intrinsic firing patterns, action-potential shapes, resting membrane potentials, input resistances, and evoked excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) did not differ between reelers and controls when data were grouped. 3. The depth distribution of intrinsic firing patterns was inverted in the reeler: intrinsically bursting (IB) neurons were found only in layer 5 in the normal mouse, but they were found exclusively in supragranular layers of the reeler cortex. 4. The spatial distribution of synaptic responses in the reeler was also inverted: very prominent IPSPs were characteristic of upper layer neurons in the normal mouse, but in the reeler similar inhibitory responses were observed predominantly in deep infragranular layers. 5. Dye injections in reeler pyramidal neurons revealed atypical morphologies, including distorted apical dendrites and cell inversion. 6. The data imply that cortical neurons develop the membrane and synaptic properties appropriate to their function, despite being malformed and mispositioned.

Astrocytic Expression of the Immunoreceptor CD300f Protects Hippocampal Neurons from Amyloid-β Oligomer Toxicity In Vitro

2017 ◽  
Vol 14 (7) ◽  
Author(s):  
Thiago Zaqueu Lima ◽  
Luis Roberto Sardinha ◽  
Joan Sayos ◽  
Luiz Eugenio Mello ◽  
Hugo Peluffo
Keyword(s):  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Toxicity In Vitro

Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

2019 ◽  
Vol 16 (2) ◽  
pp. 116-127 ◽  
Author(s):  
Ashwani Kumar ◽  
Vineet Mehta ◽  
Utkarsh Raj ◽  
Pritish Kumar Varadwaj ◽  
Malairaman Udayabanu ◽  
...  
Keyword(s):  
In Silico ◽  
Hippocampal Neurons ◽  
Symptomatic Relief ◽  
In Vitro Assays ◽  
Disease Modifying Drugs ◽  
In Silico Docking ◽  
Ache Inhibitors ◽  
Significant Difference ◽  
Disease Modifying

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer’s disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

Spastin Interacts with CRMP2 to Regulate Neurite Outgrowth by Controlling Microtubule Dynamics through Phosphorylation Modifications

2020 ◽  
Vol 19 ◽  
Author(s):  
Sumei Li ◽  
Jifeng Zhang ◽  
Jiaqi Zhang ◽  
Jiong Li ◽  
Longfei Cheng ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Neuronal Development ◽  
Phosphorylation Site ◽  
Microtubule Dynamics ◽  
Microtubule Assembly ◽  
C Terminus ◽  
Mediator Protein ◽  
Branch Formation

Aims: Our work aims to revealing the underlying microtubule mechanism of neurites outgrowth during neuronal development, and also proposes a feasible intervention pathway for reconstructing neural network connections after nerve injury. Background: Microtubule polymerization and severing are the basis for the neurite outgrowth and branch formation. Collapsin response mediator protein 2 (CRMP2) regulates axonal growth and branching as a binding partner of the tubulin heterodimer to promote microtubule assembly. And spastin participates in the growth and regeneration of neurites by severing microtubules into small segments. However, how CRMP2 and spastin cooperate to regulate neurite outgrowth by controlling the microtubule dynamics needs to be elucidated. Objective: To explore whether neurite outgrowth was mediated by coordination of CRMP2 and spastin. Method: Hippocampal neurons were cultured in vitro in 24-well culture plates for 4 days before being used to perform the transfection. Calcium phosphate was used to transfect the CRMP2 and spastin constructs and their control into the neurons. An interaction between CRMP2 and spastin was examined by using pull down, CoIP and immunofluorescence colocalization assays. And immunostaining was also performed to determine the morphology of neurites. Result: We first demonstrated that CRMP2 interacted with spastin to promote the neurite outgrowth and branch formation. Furthermore, our results identified that phosphorylation modification failed to alter the binding affinities of CRMP2 for spastin, but inhibited their binding to microtubules. CRMP2 interacted with the MTBD domain of spastin via its C-terminus, and blocking the binding sites of them inhibited the outgrowth and branch formation of neurites. In addition, we confirmed one phosphorylation site S210 at spastin in hippocampal neurons and phosphorylation spastin at site S210 promoted the neurite outgrowth but not branch formation by remodeling microtubules. Conclusion: Taken together, our data demonstrated that the interaction of CRMP2 and spastin is required for neurite outgrowth and branch formation and their interaction is not regulated by their phosphorylation.

scholarly journals H2S protects hippocampal neurons against hypoxia-reoxygenation injury by promoting RhoA phosphorylation at Ser188

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ye Chen ◽  
Jiyue Wen ◽  
Zhiwu Chen
Keyword(s):  
Endothelial Cells ◽  
Hippocampal Neurons ◽  
Glucose Deprivation ◽  
Rhoa Activity ◽  
Mercaptopyruvate Sulfurtransferase ◽  
Dependent Protein ◽  
Cerebral Vasodilatation ◽  
Reoxygenation Injury ◽  
Hypoxia Reoxygenation

AbstractInhibition of RhoA-ROCK pathway is involved in the H2S-induced cerebral vasodilatation and H2S-mediated protection on endothelial cells against oxygen-glucose deprivation/reoxygenation injury. However, the inhibitory mechanism of H2S on RhoA-ROCK pathway is still unclear. The aim of this study was to investigate the target and mechanism of H2S in inhibition of RhoA/ROCK. GST-RhoAwild and GST-RhoAS188A proteins were constructed and expressed, and were used for phosphorylation assay in vitro. Recombinant RhoAwild-pEGFP-N1 and RhoAS188A-pEGFP-N1 plasmids were constructed and transfected into primary hippocampal nerve cells (HNCs) to evaluate the neuroprotective mechanism of endothelial H2S by using transwell co-culture system with endothelial cells from cystathionine-γ-lyase knockout (CSE−/−) mice and 3-mercaptopyruvate sulfurtransferase knockout (3-MST−/−) rats, respectively. We found that NaHS, exogenous H2S donor, promoted RhoA phosphorylation at Ser188 in the presence of cGMP-dependent protein kinase 1 (PKG1) in vitro. Besides, both exogenous and endothelial H2S facilitated the RhoA phosphorylation at Ser188 in HNCs, which induced the reduction of RhoA activity and membrane transposition, as well as ROCK2 activity and expression. To further investigate the role of endothelial H2S on RhoA phosphorylation, we detected H2S release from ECs of CSE+/+ and CSE−/− mice, and 3-MST+/+ and 3-MST−/− rats, respectively, and found that H2S produced by ECs in the culture medium is mainly catalyzed by CSE synthase. Moreover, we revealed that both endothelial H2S, mainly catalyzed by CSE, and exogenous H2S protected the HNCs against hypoxia-reoxygenation injury via phosphorylating RhoA at Ser188.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties

2020 ◽  
Vol 54 (01) ◽  
pp. 37-46
Author(s):  
Kristina Friedland ◽  
Giacomo Silani ◽  
Anita Schuwald ◽  
Carola Stockburger ◽  
Egon Koch ◽  
...  
Keyword(s):  
Essential Oil ◽  
Hippocampal Neurons ◽  
Day Treatment ◽  
Neuronal Cell ◽  
Antidepressant Activity ◽  
In Vivo Models ◽  
Antidepressant Effects ◽  
Primary Hippocampal Neurons

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology—resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function—we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. Results The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Conclusion Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

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