Paradoxical signaling regulates structural plasticity in dendritic spines

Transient spine enlargement (3- to 5-min timescale) is an important event associated with the structural plasticity of dendritic spines. Many of the molecular mechanisms associated with transient spine enlargement have been identified experimentally. Here, we use a systems biology approach to construct a mathematical model of biochemical signaling and actin-mediated transient spine expansion in response to calcium influx caused by NMDA receptor activation. We have identified that a key feature of this signaling network is the paradoxical signaling loop. Paradoxical components act bifunctionally in signaling networks, and their role is to control both the activation and the inhibition of a desired response function (protein activity or spine volume). Using ordinary differential equation (ODE)-based modeling, we show that the dynamics of different regulators of transient spine expansion, including calmodulin-dependent protein kinase II (CaMKII), RhoA, and Cdc42, and the spine volume can be described using paradoxical signaling loops. Our model is able to capture the experimentally observed dynamics of transient spine volume. Furthermore, we show that actin remodeling events provide a robustness to spine volume dynamics. We also generate experimentally testable predictions about the role of different components and parameters of the network on spine dynamics.

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Paradoxical signaling regulates structural plasticity in dendritic spines

10.1101/050492 ◽

2016 ◽

Author(s):

Padmini Rangamani ◽

Michael G. Levy ◽

Shahid M. Khan ◽

George Oster

Keyword(s):

Differential Equation ◽

Dendritic Spines ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Structural Plasticity ◽

Receptor Activation ◽

Protein Activity ◽

Nmda Receptor Activation ◽

Spine Dynamics

AbstractTransient spine enlargement (3-5 min timescale) is an important event associated with the structural plasticity of dendritic spines. Many of the molecular mechanisms associated with transient spine enlargement have been identified experimentally. Here, we use a systems biology approach to construct a mathematical model of biochemical signaling and actin-mediated transient spine expansion in response to calcium-influx due to NMDA receptor activation. We have identified that a key feature of this signaling network is the paradoxical signaling loop. Paradoxical components act bifunctionally in signaling networks and their role is to control both the activation and inhibition of a desired response function (protein activity or spine volume). Using ordinary differential equation (ODE)-based modeling, we show that the dynamics of different regulators of transient spine expansion including CaMKII, RhoA, and Cdc42 and the spine volume can be described using paradoxical signaling loops. Our model is able to capture the experimentally observed dynamics of transient spine volume. Furthermore, we show that actin remodeling events provide a robustness to spine volume dynamics. We also generate experimentally testable predictions about the role of different components and parameters of the network on spine dynamics.

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Regulation of dendritic spine growth through activity-dependent recruitment of the brain-enriched Na+/H+ exchanger NHE5

Molecular Biology of the Cell ◽

10.1091/mbc.e11-01-0066 ◽

2011 ◽

Vol 22 (13) ◽

pp. 2246-2257 ◽

Cited By ~ 32

Author(s):

Graham H. Diering ◽

Fergil Mills ◽

Shernaz X. Bamji ◽

Masayuki Numata

Keyword(s):

Nmda Receptor ◽

Dendritic Spines ◽

Dendritic Spine ◽

Molecular Mechanisms ◽

Fluorescent Protein ◽

Receptor Activation ◽

Neuronal Activation ◽

Activity Dependent ◽

The Brain ◽

Nmda Receptor Activation

Subtle changes in cellular and extracellular pH within the physiological range have profound impacts on synaptic activities. However, the molecular mechanisms underlying local pH regulation at synapses and their influence on synaptic structures have not been elucidated. Dendritic spines undergo dynamic structural changes in response to neuronal activation, which contributes to induction and long-term maintenance of synaptic plasticity. Although previous studies have indicated the importance of cytoskeletal rearrangement, vesicular trafficking, cell signaling, and adhesion in this process, much less is known about the involvement of ion transporters. In this study we demonstrate that N-methyl-d-aspartate (NMDA) receptor activation causes recruitment of the brain-enriched Na+/H+ exchanger NHE5 from endosomes to the plasma membrane. Concomitantly, real-time imaging of green fluorescent protein–tagged NHE5 revealed that NMDA receptor activation triggers redistribution of NHE5 to the spine head. We further show that neuronal activation causes alkalinization of dendritic spines following the initial acidification, and suppression of NHE5 significantly retards the activity-induced alkalinization. Perturbation of NHE5 function induces spontaneous spine growth, which is reversed by inhibition of NMDA receptors. In contrast, overexpression of NHE5 inhibits spine growth in response to neuronal activity. We propose that NHE5 constrains activity-dependent dendritic spine growth via a novel, pH-based negative-feedback mechanism.

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Faculty Opinions recommendation of Estradiol-induced enhancement of fear extinction in female rats: The role of NMDA receptor activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733261946.793567213 ◽

2019 ◽

Author(s):

Amy Milton

Keyword(s):

Nmda Receptor ◽

Receptor Activation ◽

Fear Extinction ◽

Female Rats ◽

Nmda Receptor Activation

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Transient Removal of Extracellular Mg2+ Elicits Persistent Suppression of LTP at Hippocampal CA1 Synapses Via PKC Activation

Journal of Neurophysiology ◽

10.1152/jn.2000.84.3.1279 ◽

2000 ◽

Vol 84 (3) ◽

pp. 1279-1288 ◽

Cited By ~ 17

Author(s):

Kuei-Sen Hsu ◽

Wen-Chia Ho ◽

Chiung-Chun Huang ◽

Jing-Jane Tsai

Keyword(s):

Nmda Receptor ◽

Protein Kinase ◽

Molecular Mechanisms ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Receptor Activation ◽

Suppressive Effect ◽

Dependent Protein Kinase ◽

Dependent Protein

Previous work has shown that seizure-like activity can disrupt the induction of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecular mechanisms underlying this process better, a set of studies was implemented in area CA1 of rat hippocampal slices using extracellular recording methods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg2+-free artificial cerebrospinal fluid (ACSF) exhibited a persistent suppression of LTP induction. This effect lasted between 2 and 3 h after normal ACSF replacement and was specifically inhibited by N-methyl-d-aspartate (NMDA) receptor antagonistd-2-amino-5-phosphovaleric acid (d-APV) and L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In addition, this suppressive effect was specifically blocked by the selective protein kinase C (PKC) inhibitor NPC-15437. However, neither Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP-dependent protein kinase inhibitor Rp-adenosine 3′,5′-cyclic monophosphothioate (Rp-cAMPS) affected this suppressive effect. This persistent suppression of LTP was not secondary to the long-lasting changes in NMDA receptor activation, because the isolated NMDA receptor–mediated responses did not show a long-term enhancement in response to a 30-min Mg2+-free ACSF application. Additionally, in prior Mg2+-free ACSF–treated slices, the entire frequency-response curve of LTP and long-term depression (LTD) is shifted systematically to favor LTD. These results suggest that the increase of Ca2+ influx through NMDA channels and L-type VOCCs in turn triggering a PKC-dependent signaling cascade is a possible cellular basis underlying this seizure-like activity-induced inhibition of LTP.

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Chapter 23 Regulation of immediate early genes in brain: role of NMDA receptor activation

Progress in Brain Research - The Developing Brain ◽

10.1016/s0079-6123(08)63184-2 ◽

1990 ◽

pp. 277-285 ◽

Cited By ~ 25

Author(s):

Paul F. Worley ◽

Andrew J. Cole ◽

David W. Saffen ◽

Jay M. Baraban

Keyword(s):

Nmda Receptor ◽

Immediate Early Genes ◽

Receptor Activation ◽

Immediate Early ◽

Early Genes ◽

Nmda Receptor Activation

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The Roles of CaMKII and F-Actin in the Structural Plasticity of Dendritic Spines: A Potential Molecular Identity of a Synaptic Tag?

Physiology ◽

10.1152/physiol.00029.2009 ◽

2009 ◽

Vol 24 (6) ◽

pp. 357-366 ◽

Cited By ~ 86

Author(s):

Kenichi Okamoto ◽

Miquel Bosch ◽

Yasunori Hayashi

Keyword(s):

Dendritic Spines ◽

Binding Capacity ◽

Direct Interaction ◽

Structural Plasticity ◽

Long Term Potentiation ◽

Postsynaptic Protein ◽

Term Potentiation ◽

The Status ◽

Dependent Protein ◽

Protein Binding Capacity

Ca2+/calmodulin-dependent protein kinase II (CaMKII) and actin are two crucial molecules involved in long-term potentiation (LTP). In addition to its signaling function, CaMKII plays a structural role via direct interaction with actin filaments, thus coupling functional and structural plasticity in dendritic spines. The status of F-actin, regulated by CaMKII, determines the postsynaptic protein binding capacity and thus may act as a synaptic tag that consolidates LTP.

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Postsynaptic protein mobility in dendritic spines: Long-term regulation by synaptic NMDA receptor activation

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2006.01.010 ◽

2006 ◽

Vol 31 (4) ◽

pp. 702-712 ◽

Cited By ~ 87

Author(s):

Kamal Sharma ◽

Dan K. Fong ◽

Ann Marie Craig

Keyword(s):

Nmda Receptor ◽

Dendritic Spines ◽

Receptor Activation ◽

Protein Mobility ◽

Postsynaptic Protein ◽

Nmda Receptor Activation

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Molecular mechanisms of GABAB receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator

Biochemical Society Transactions ◽

10.1042/bst0320871 ◽

2004 ◽

Vol 32 (5) ◽

pp. 871-872 ◽

Cited By ~ 15

Author(s):

V. Binet ◽

C. Goudet ◽

C. Brajon ◽

L. Le Corre ◽

F. Acher ◽

...

Keyword(s):

G Protein ◽

Mechanism Of Action ◽

Molecular Mechanisms ◽

Gabab Receptor ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Class Iii ◽

G Protein Coupled ◽

New Strategies

The GABAB (γ-aminobutyric acid-B) receptor is composed of two subunits, GABAB1 and GABAB2. Both subunits share structural homology with other class-III G-protein-coupled receptors. They contain two main domains, a heptahelical domain typical of all G-protein-coupled receptors and a large ECD (extracellular domain). It has not been demonstrated whether the association of these two subunits is always required for function. However, GABAB2 plays a major role in coupling with G-proteins, and GABAB1 has been shown to bind GABA. To date, only ligands interacting with GABAB1-ECD have been identified. In the present study, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABAB receptor. We have shown that it can weakly activate the wild-type GABAB receptor, but also the GABAB2 expressed alone, thus being the first described agonist of GABAB2. CGP7930 retains its weak agonist activity on a GABAB2 subunit deleted of its ECD. Thus the heptahelical domain of GABAB2 behaves similar to a rhodopsin-like receptor. These results open new strategies for studying the mechanism of activation of GABAB receptor and examine any possible role of GABAB2.

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