scholarly journals CD44: a novel synaptic cell adhesion molecule regulating structural and functional plasticity of dendritic spines

2016 ◽  
Vol 27 (25) ◽  
pp. 4055-4066 ◽  
Author(s):  
Matylda Roszkowska ◽  
Anna Skupien ◽  
Tomasz Wójtowicz ◽  
Anna Konopka ◽  
Adam Gorlewicz ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Rho Gtpases ◽  
Hippocampal Neurons ◽  
Synaptic Function ◽  
Adult Brain ◽  
Spine Shape ◽  
Neuronal Stimulation ◽  
And Function

Synaptic cell adhesion molecules regulate signal transduction, synaptic function, and plasticity. However, their role in neuronal interactions with the extracellular matrix (ECM) is not well understood. Here we report that the CD44, a transmembrane receptor for hyaluronan, modulates synaptic plasticity. High-resolution ultrastructural analysis showed that CD44 was localized at mature synapses in the adult brain. The reduced expression of CD44 affected the synaptic excitatory transmission of primary hippocampal neurons, simultaneously modifying dendritic spine shape. The frequency of miniature excitatory postsynaptic currents decreased, accompanied by dendritic spine elongation and thinning. These structural and functional alterations went along with a decrease in the number of presynaptic Bassoon puncta, together with a reduction of PSD-95 levels at dendritic spines, suggesting a reduced number of functional synapses. Lack of CD44 also abrogated spine head enlargement upon neuronal stimulation. Moreover, our results indicate that CD44 contributes to proper dendritic spine shape and function by modulating the activity of actin cytoskeleton regulators, that is, Rho GTPases (RhoA, Rac1, and Cdc42). Thus CD44 appears to be a novel molecular player regulating functional and structural plasticity of dendritic spines.

Dendritic Spine Remodeling After Spinal Cord Injury Alters Neuronal Signal Processing

2009 ◽  
Vol 102 (4) ◽  
pp. 2396-2409 ◽  
Author(s):  
Andrew M. Tan ◽  
Jin-Sung Choi ◽  
Stephen G. Waxman ◽  
Bryan C. Hains
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Synaptic Transmission ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Nociceptive Neurons ◽  
Spine Shape ◽  
Cord Injury ◽  
Dendritic Spine Morphology ◽  
Neuronal Signal

Central sensitization, a prolonged hyperexcitability of dorsal horn nociceptive neurons, is a major contributor to abnormal pain processing after spinal cord injury (SCI). Dendritic spines are micron-sized dendrite protrusions that can regulate the efficacy of synaptic transmission. Here we used a computational approach to study whether changes in dendritic spine shape, density, and distribution can individually, or in combination, adversely modify the input–output function of a postsynaptic neuron to create a hyperexcitable neuronal state. The results demonstrate that a conversion from thin-shaped to more mature, mushroom-shaped spine structures results in enhanced synaptic transmission and fidelity, improved frequency-following ability, and reduced inhibitory gating effectiveness. Increasing the density and redistributing spines toward the soma results in a greater probability of action potential activation. Our results demonstrate that changes in dendritic spine morphology, documented in previous studies on spinal cord injury, contribute to the generation of pain following SCI.

scholarly journals O-GlcNAc transferase regulates excitatory synapse maturity

2017 ◽  
Vol 114 (7) ◽  
pp. 1684-1689 ◽  
Author(s):  
Olof Lagerlöf ◽  
Gerald W. Hart ◽  
Richard L. Huganir
Keyword(s):  
Food Intake ◽  
Dendritic Spines ◽  
Protein Function ◽  
Postsynaptic Density ◽  
Synaptic Function ◽  
Excitatory Synapse ◽  
Excitatory Synapses ◽  
Intracellular Proteins ◽  
Neuronal Stimulation ◽  
Glcnac Transferase

Experience-driven synaptic plasticity is believed to underlie adaptive behavior by rearranging the way neuronal circuits process information. We have previously discovered that O-GlcNAc transferase (OGT), an enzyme that modifies protein function by attaching β–N-acetylglucosamine (GlcNAc) to serine and threonine residues of intracellular proteins (O-GlcNAc), regulates food intake by modulating excitatory synaptic function in neurons in the hypothalamus. However, how OGT regulates excitatory synapse function is largely unknown. Here we demonstrate that OGT is enriched in the postsynaptic density of excitatory synapses. In the postsynaptic density, O-GlcNAcylation on multiple proteins increased upon neuronal stimulation. Knockout of the OGT gene decreased the synaptic expression of the AMPA receptor GluA2 and GluA3 subunits, but not the GluA1 subunit. The number of opposed excitatory presynaptic terminals was sharply reduced upon postsynaptic knockout of OGT. There were also fewer and less mature dendritic spines on OGT knockout neurons. These data identify OGT as a molecular mechanism that regulates synapse maturity.

scholarly journals Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor–dependent manner

2006 ◽  
Vol 172 (3) ◽  
pp. 453-467 ◽  
Author(s):  
Vanessa Schubert ◽  
Jorge Santos Da Silva ◽  
Carlos G. Dotti
Keyword(s):  
Actin Cytoskeleton ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Excitatory Synapses ◽  
Dependent Manner ◽  
Rhoa Activity ◽  
Spine Shape ◽  
Local Reduction ◽  
Dendritic Spine Morphology

Actin is the major cytoskeletal source of dendritic spines, which are highly specialized protuberances on the neuronal surface where excitatory synaptic transmission occurs (Harris, K.M., and S.B. Kater. 1994. Annu. Rev. Neurosci. 17:341–371; Yuste, R., and D.W. Tank. 1996. Neuron. 16:701–716). Stimulation of excitatory synapses induces changes in spine shape via localized rearrangements of the actin cytoskeleton (Matus, A. 2000. Science. 290:754–758; Nagerl, U.V., N. Eberhorn, S.B. Cambridge, and T. Bonhoeffer. 2004. Neuron. 44:759–767). However, what remains elusive are the precise molecular mechanisms by which different neurotransmitter receptors forward information to the underlying actin cytoskeleton. We show that in cultured hippocampal neurons as well as in whole brain synaptosomal fractions, RhoA associates with glutamate receptors (GluRs) at the spine plasma membrane. Activation of ionotropic GluRs leads to the detachment of RhoA from these receptors and its recruitment to metabotropic GluRs. Concomitantly, this triggers a local reduction of RhoA activity, which, in turn, inactivates downstream kinase RhoA-specific kinase, resulting in restricted actin instability and dendritic spine collapse. These data provide a direct mechanistic link between neurotransmitter receptor activity and the changes in spine shape that are thought to play a crucial role in synaptic strength.

scholarly journals Hippocampal Dendritic Spines Are Segregated Depending on Their Actin Polymerization

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Nuria Domínguez-Iturza ◽  
María Calvo ◽  
Marion Benoist ◽  
José Antonio Esteban ◽  
Miguel Morales
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Actin Polymerization ◽  
Close Contact ◽  
Postsynaptic Membrane ◽  
Actin Dynamics ◽  
Filamentous Actin ◽  
Virtual Absence ◽  
Spine Shape ◽  
Mobile Fraction

Dendritic spines are mushroom-shaped protrusions of the postsynaptic membrane. Spines receive the majority of glutamatergic synaptic inputs. Their morphology, dynamics, and density have been related to synaptic plasticity and learning. The main determinant of spine shape is filamentous actin. Using FRAP, we have reexamined the actin dynamics of individual spines from pyramidal hippocampal neurons, both in cultures and in hippocampal organotypic slices. Our results indicate that, in cultures, the actin mobile fraction is independently regulated at the individual spine level, and mobile fraction values do not correlate with either age or distance from the soma. The most significant factor regulating actin mobile fraction was the presence of astrocytes in the culture substrate. Spines from neurons growing in the virtual absence of astrocytes have a more stable actin cytoskeleton, while spines from neurons growing in close contact with astrocytes show a more dynamic cytoskeleton. According to their recovery time, spines were distributed into two populations with slower and faster recovery times, while spines from slice cultures were grouped into one population. Finally, employing fast lineal acquisition protocols, we confirmed the existence of loci with high polymerization rates within the spine.

scholarly journals Regulation of cell–cell adhesion by the cadherin–catenin complex

2008 ◽  
Vol 36 (2) ◽  
pp. 149-155 ◽  
Author(s):  
W. James Nelson
Keyword(s):  
Cell Adhesion ◽  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
De Novo ◽  
Cytoplasmic Proteins ◽  
Cytoskeleton Reorganization ◽  
Dependent Cell ◽  
And Function ◽  
Cell Cell

Ca2+-dependent cell–cell adhesion is regulated by the cadherin family of cell adhesion proteins. Cadherins form trans-interactions on opposing cell surfaces which result in weak cell–cell adhesion. Stronger cell–cell adhesion occurs by clustering of cadherins and through changes in the organization of the actin cytoskeleton. Although cadherins were thought to bind directly to the actin cytoskeleton through cytoplasmic proteins, termed α- and β-catenin, recent studies with purified proteins indicate that the interaction is not direct, and instead an allosteric switch in α-catenin may mediate actin cytoskeleton reorganization. Organization and function of the cadherin–catenin complex are additionally regulated by phosphorylation and endocytosis. Direct studies of cell–cell adhesion has revealed that the cadherin–catenin complex and the underlying actin cytoskeleton undergo a series of reorganizations that are controlled by the Rho GTPases, Rac1 and RhoA, that result in the expansion and completion of cell–cell adhesion. In the present article, in vitro protein assembly studies and live-cell studies of de novo cell–cell adhesion are discussed in the context of how the cadherin–catenin complex and the actin cytoskeleton regulate cell–cell adhesion.

Drebrin A regulates dendritic spine plasticity and synaptic function in mature cultured hippocampal neurons

2009 ◽  
Vol 122 (4) ◽  
pp. 524-534 ◽  
Author(s):  
A. Ivanov ◽  
M. Esclapez ◽  
C. Pellegrino ◽  
T. Shirao ◽  
L. Ferhat
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Synaptic Function ◽  
Spine Plasticity ◽  
Cultured Hippocampal Neurons

scholarly journals Neuronal hibernation following hippocampal demyelination

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Selva Baltan ◽  
Safdar S. Jawaid ◽  
Anthony M. Chomyk ◽  
Grahame J. Kidd ◽  
Jacqueline Chen ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Mammalian Brain ◽  
Gene Transcript ◽  
Ca1 Neurons

AbstractCognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca2+-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.

scholarly journals Overexpression of Tropomyosin Isoform Tpm3.1 Does Not Alter Synaptic Function in Hippocampal Neurons

2021 ◽  
Vol 22 (17) ◽  
pp. 9303
Author(s):  
Chanchanok Chaichim ◽  
Tamara Tomanic ◽  
Holly Stefen ◽  
Esmeralda Paric ◽  
Lucy Gamaroff ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Brain Slices ◽  
Structure And Function ◽  
Spine Morphology ◽  
Dendritic Spine Morphology ◽  
And Function ◽  
Cultured Hippocampal Neurons

Tropomyosin (Tpm) has been regarded as the master regulator of actin dynamics. Tpms regulate the binding of the various proteins involved in restructuring actin. The actin cytoskeleton is the predominant cytoskeletal structure in dendritic spines. Its regulation is critical for spine formation and long-term activity-dependent changes in synaptic strength. The Tpm isoform Tpm3.1 is enriched in dendritic spines, but its role in regulating the synapse structure and function is not known. To determine the role of Tpm3.1, we studied the synapse structure and function of cultured hippocampal neurons from transgenic mice overexpressing Tpm3.1. We recorded hippocampal field excitatory postsynaptic potentials (fEPSPs) from brain slices to examine if Tpm3.1 overexpression alters long-term synaptic plasticity. Tpm3.1-overexpressing cultured neurons did not show a significantly altered dendritic spine morphology or synaptic activity. Similarly, we did not observe altered synaptic transmission or plasticity in brain slices. Furthermore, expression of Tpm3.1 at the postsynaptic compartment does not increase the local F-actin levels. The results suggest that although Tpm3.1 localises to dendritic spines in cultured hippocampal neurons, it does not have any apparent impact on dendritic spine morphology or function. This is contrary to the functional role of Tpm3.1 previously observed at the tip of growing neurites, where it increases the F-actin levels and impacts growth cone dynamics.

scholarly journals Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hao Chen ◽  
Jing Tian ◽  
Lan Guo ◽  
Heng Du
Keyword(s):  
Atp Synthase ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Caspase 3 ◽  
Mitochondrial Pathway ◽  
Spine Injury ◽  
F1fo Atp Synthase ◽  
Atp Production ◽  
Oligomycin A

Abstract Dendritic spine injury underlies synaptic failure in many neurological disorders. Mounting evidence suggests a mitochondrial pathway of local nonapoptotic caspase signaling in mediating spine pruning. However, it remains unclear whether this caspase signaling plays a key role in spine loss when severe mitochondrial functional defects are present. The answer to this question is critical especially for some pathological states, in which mitochondrial deficits are prominent and difficult to fix. F1Fo ATP synthase is a pivotal mitochondrial enzyme and the dysfunction of this enzyme involves in diseases with spinopathy. Here, we inhibited F1Fo ATP synthase function in primary cultured hippocampal neurons by using non-lethal oligomycin A treatment. Oligomycin A induced mitochondrial defects including collapsed mitochondrial membrane potential, dissipated ATP production, and elevated reactive oxygen species (ROS) production. In addition, dendritic mitochondria underwent increased fragmentation and reduced positioning to dendritic spines along with increased caspase 3 cleavage in dendritic shaft and spines in response to oligomycin A. Concurring with these dendritic mitochondrial changes, oligomycin A-insulted neurons displayed spine loss and altered spine architecture. Such oligomycin A-mediated changes in dendritic spines were substantially prevented by the inhibition of caspase activation by using a pan-caspase inhibitor, quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh). Of note, the administration of Q-VD-OPh showed no protective effect on oligomycin A-induced mitochondrial dysfunction. Our findings suggest a pivotal role of caspase 3 signaling in mediating spine injury and the modulation of caspase 3 activation may benefit neurons from spine loss in diseases, at least, in those with F1Fo ATP synthase defects.

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