scholarly journals A Multi-State Model of the CaMKII Dodecamer Suggests a Role for Calmodulin in Maintenance of Autophosphorylation

2019 ◽  
Author(s):  
Matthew C. Pharris ◽  
Thomas M. Bartol ◽  
Terrence J. Sejnowski ◽  
Mary B. Kennedy ◽  
Melanie I. Stefan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Conformational Changes ◽  
Computational Models ◽  
Molecular Mechanisms ◽  
Memory Function ◽  
Rule Based ◽  
Calcium Calmodulin Dependent ◽  
Neuronal Connections ◽  
Rule Based Approach

AbstractCa2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme’s twelve subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of the twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other’s binding to CaMKII. Our results suggest a functional mechanism for the so-called “CaM trapping” phenomenon, such that Ca2+/CaM structurally excludes phosphatase binding and thereby prolongs CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity.Author summaryIn the hippocampus, the dynamic fluctuation in size and strength of neuronal connections is thought to underlie learning and memory processes. These fluctuations, called synaptic plasticity, are in-part regulated by the protein calcium/calmodulin-dependent kinase II (CaMKII). During synaptic plasticity, CaMKII becomes activated in the presence of calcium ions (Ca2+) and calmodulin (CaM), allowing it to interact enzymatically with downstream binding partners. Interestingly, activated CaMKII can phosphorylate itself, resulting in state changes that allow CaMKII to be functionally active independent of Ca2+/CaM. Phosphorylation of CaMKII at Thr-286/287 has been shown to be a critical component of learning and memory. To explore the molecular mechanisms that regulate the activity of CaMKII holoenzymes, we use a rule-based approach that reduces computational complexity normally associated with representing the wide variety of functional states that a CaMKII holoenzyme can adopt. Using this approach we observe regulatory mechanisms that might be obscured by reductive approaches. Our results newly suggest that CaMKII phosphorylation at Thr-286/287 is stabilized by a mechanism in which CaM structurally excludes phosphatase binding at that site.

scholarly journals Neuronal megalin mediates synaptic plasticity—a novel mechanism underlying intellectual disabilities in megalin gene pathologies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
João R Gomes ◽  
Andrea Lobo ◽  
Renata Nogueira ◽  
Ana F Terceiro ◽  
Susete Costelha ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Intellectual Disabilities ◽  
Learning And Memory ◽  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Cell Surface Receptor ◽  
Neuronal Cultures

Abstract Donnai-Barrow syndrome, a genetic disorder associated to LRP2 (low-density lipoprotein receptor 2/megalin) mutations, is characterized by unexplained neurological symptoms and intellectual deficits. Megalin is a multifunctional endocytic clearance cell-surface receptor, mostly described in epithelial cells. This receptor is also expressed in the CNS, mainly in neurons, being involved in neurite outgrowth and neuroprotective mechanisms. Yet, the mechanisms involved in the regulation of megalin in the CNS are poorly understood. Using transthyretin knockout mice, a megalin ligand, we found that transthyretin positively regulates neuronal megalin levels in different CNS areas, particularly in the hippocampus. Transthyretin is even able to rescue megalin downregulation in transthyretin knockout hippocampal neuronal cultures, in a positive feedback mechanism via megalin. Importantly, transthyretin activates a regulated intracellular proteolysis mechanism of neuronal megalin, producing an intracellular domain, which is translocated to the nucleus, unveiling megalin C-terminal as a potential transcription factor, able to regulate gene expression. We unveil that neuronal megalin reduction affects physiological neuronal activity, leading to decreased neurite number, length and branching, and increasing neuronal susceptibility to a toxic insult. Finally, we unravel a new unexpected role of megalin in synaptic plasticity, by promoting the formation and maturation of dendritic spines, and contributing for the establishment of active synapses, both in in vitro and in vivo hippocampal neurons. Moreover, these structural and synaptic roles of megalin impact on learning and memory mechanisms, since megalin heterozygous mice show hippocampal-related memory and learning deficits in several behaviour tests. Altogether, we unveil a complete novel role of megalin in the physiological neuronal activity, mainly in synaptic plasticity with impact in learning and memory. Importantly, we contribute to disclose the molecular mechanisms underlying the cognitive and intellectual disabilities related to megalin gene pathologies.

scholarly journals Animating Cognitive Models and Architectures: A Rule-Based Approach

10.29007/wjwz ◽  
2018 ◽  
Author(s):  
Nada Sharaf ◽  
Slim Abdennadher ◽  
Thom Fruehwirth ◽  
Daniel Gall
Keyword(s):  
Intelligent Agents ◽  
Computational Models ◽  
Cognitive Architecture ◽  
Proof Of Concept ◽  
Cognitive Agent ◽  
Cognitive Architectures ◽  
Learning Problem ◽  
Rule Based ◽  
Computational Psychology ◽  
Rule Based Approach

Computational psychology provides computational models exploring different aspects of cognition. A cognitive architecture includes the basic aspects of any cognitive agent. It consists of different correlated modules. In general, cognitive architectures provide the needed layouts for building intelligent agents. The paper presents the a rule-based approach to visually animate the simulations of models done through cognitive architectures. As a proof of concept, simulations through Adaptive Control of Thought-Rational (ACT-R) were animated. ACT-R is a well-known cognitive architecture. It was deployed to create models in different fields including, among others, learning, problem solving and languages.

scholarly journals Neuromodulators and Long-Term Synaptic Plasticity in Learning and Memory: A Steered-Glutamatergic Perspective

2019 ◽  
Vol 9 (11) ◽  
pp. 300 ◽  
Author(s):  
Amjad Bazzari ◽  
H. Parri
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Current Evidence ◽  
Metabotropic Receptors ◽  
Neuronal Connections ◽  
Molecular Substrates ◽  
Neuronal Encoding ◽  
Review Current

The molecular pathways underlying the induction and maintenance of long-term synaptic plasticity have been extensively investigated revealing various mechanisms by which neurons control their synaptic strength. The dynamic nature of neuronal connections combined with plasticity-mediated long-lasting structural and functional alterations provide valuable insights into neuronal encoding processes as molecular substrates of not only learning and memory but potentially other sensory, motor and behavioural functions that reflect previous experience. However, one key element receiving little attention in the study of synaptic plasticity is the role of neuromodulators, which are known to orchestrate neuronal activity on brain-wide, network and synaptic scales. We aim to review current evidence on the mechanisms by which certain modulators, namely dopamine, acetylcholine, noradrenaline and serotonin, control synaptic plasticity induction through corresponding metabotropic receptors in a pathway-specific manner. Lastly, we propose that neuromodulators control plasticity outcomes through steering glutamatergic transmission, thereby gating its induction and maintenance.

scholarly journals Electroacupuncture Ameliorates Learning and Memory and Improves Synaptic Plasticity via Activation of the PKA/CREB Signaling Pathway in Cerebral Hypoperfusion

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Cai-Xia Zheng ◽  
Min Lu ◽  
Ya-Bi Guo ◽  
Feng-Xia Zhang ◽  
Hua Liu ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Signaling Pathway ◽  
Learning And Memory ◽  
Molecular Mechanisms ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Cerebral Hypoperfusion ◽  
Electrophysiological Recording ◽  
Learning And Memory Deficits ◽  
Creb Pathway

Electroacupuncture (EA) has shown protective effects on cognitive decline. However, the underlying molecular mechanisms are ill-understood. The present study was undertaken to determine whether the cognitive function was ameliorated in cerebral hypoperfusion rats following EA and to investigate the role of PKA/CREB pathway. We used a rat 2-vessel occlusion (2VO) model and delivered EA at Baihui (GV20) and Dazhui (GV14) acupoints. Morris water maze (MWM) task, electrophysiological recording, Golgi silver stain, Nissl stain, Western blot, and real-time PCR were employed. EA significantly (1) ameliorated the spatial learning and memory deficits, (2) alleviated long-term potentiation (LTP) impairment and the reduction of dendritic spine density, (3) suppressed the decline of phospho-CREB (pCREB) protein, brain-derived neurotrophic factor (BDNF) protein, and microRNA132 (miR132), and (4) reduced the increase of p250GAP protein of 2VO rats. These changes were partially blocked by a selective protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89), suggesting that the PKA/CREB pathway is potentially involved in the effects of EA. Moreover, any significant damage to the pyramidal cell layer of CA1 subregion was absent. These results demonstrated that EA could ameliorate learning and memory deficits and alleviate hippocampal synaptic plasticity impairment of cerebral hypoperfusion rats, potentially mediated by PKA/CREB signaling pathway.

scholarly journals GRIP1 regulates synaptic plasticity and learning and memory

2020 ◽  
Vol 117 (40) ◽  
pp. 25085-25091
Author(s):  
Han L. Tan ◽  
Shu-Ling Chiu ◽  
Qianwen Zhu ◽  
Richard L. Huganir
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Postsynaptic Membrane ◽  
Interacting Protein ◽  
Synaptic Targeting ◽  
Brain Functions ◽  
Ampar Trafficking

Hebbian plasticity is a key mechanism for higher brain functions, such as learning and memory. This form of synaptic plasticity primarily involves the regulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) abundance and properties, whereby AMPARs are inserted into synapses during long-term potentiation (LTP) or removed during long-term depression (LTD). The molecular mechanisms underlying AMPAR trafficking remain elusive, however. Here we show that glutamate receptor interacting protein 1 (GRIP1), an AMPAR-binding protein shown to regulate the trafficking and synaptic targeting of AMPARs, is required for LTP and learning and memory. GRIP1 is recruited into synapses during LTP, and deletion of Grip1 in neurons blocks synaptic AMPAR accumulation induced by glycine-mediated depolarization. In addition, Grip1 knockout mice exhibit impaired hippocampal LTP, as well as deficits in learning and memory. Mechanistically, we find that phosphorylation of serine-880 of the GluA2 AMPAR subunit (GluA2-S880) is decreased while phosphorylation of tyrosine-876 on GluA2 (GluA2-Y876) is elevated during chemically induced LTP. This enhances the strength of the GRIP1–AMPAR association and, subsequently, the insertion of AMPARs into the postsynaptic membrane. Together, these results demonstrate an essential role of GRIP1 in regulating AMPAR trafficking during synaptic plasticity and learning and memory.

Continuous VA deficiency during postnatal development decreases rat learning and memory function via excitatory Ca2+neuron

2010 ◽  
Vol 34 (8) ◽  
pp. S18-S18
Author(s):  
Wei Jiang ◽  
Enyi Wen ◽  
Min Gong ◽  
Yang Bi ◽  
Xiaojuan Zhang ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Learning And Memory ◽  
Memory Function

A Brief Survey on Text Classification Using Various Machine Learning Techniques

2018 ◽  
Vol 8 (1) ◽  
pp. 14
Author(s):  
Padmavathi .S ◽  
M. Chidambaram
Keyword(s):  
Machine Learning ◽  
Text Classification ◽  
Fixed Number ◽  
Machine Learning Techniques ◽  
Online Information ◽  
Rule Based ◽  
Learning Techniques ◽  
Machine Learning Approach ◽  
Rule Based Approach

Text classification has grown into more significant in managing and organizing the text data due to tremendous growth of online information. It does classification of documents in to fixed number of predefined categories. Rule based approach and Machine learning approach are the two ways of text classification. In rule based approach, classification of documents is done based on manually defined rules. In Machine learning based approach, classification rules or classifier are defined automatically using example documents. It has higher recall and quick process. This paper shows an investigation on text classification utilizing different machine learning techniques.

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