scholarly journals Long-term Pannexin 1 Ablation Produces an Imbalance Between Small Rho-GTPases Activity and Actin Polymerization Leading to Structural and Functional Modifications in Hippocampal Neurons

2022 ◽  
Author(s):  
Carolina Flores-Muñoz ◽  
Francisca García-Rojas ◽  
Miguel A. Perez ◽  
Odra Santander ◽  
Elena Mery ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Hippocampal Neurons ◽  
Actin Polymerization ◽  
Adult Brain ◽  
Compensatory Mechanisms ◽  
Ca1 Neurons ◽  
Pannexin 1 ◽  
Small Rho Gtpases ◽  
Memory Flexibility ◽  
Cytoskeleton Dynamics

Abstract Enhanced activity and overexpression of Pannexin 1 (PANX1) channels contribute to neuronal pathologies, such as epilepsy and Alzheimer’s disease (AD). In the hippocampus, the PANX1 channel ablation alters glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, PANX1-knockout (PANX1-KO) mice still preserve the ability to learn, suggesting that compensatory mechanisms work to stabilize neuronal activity. Here, we show that the absence of PANX1 in the adult brain promotes a series of structural and functional modifications in PANX1-KO CA1 hippocampal synapses, preserving spontaneous activity. Adult CA1 neurons of PANX1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and multiple synaptic contacts compared to the WT condition. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in actin polymerization and an imbalance between Rac1 and RhoA GTPase activity is observed in the absence of PANX1. Our findings highlight a novel interaction between PANX1, actin, and small Rho GTPases, which appear to be relevant for synapse stability.

scholarly journals Long-term Pannexin 1 ablation promotes structural and functional modifications in hippocampal neurons through the regulation of actin cytoskeleton and Rho GTPases activity.

2021 ◽  
Author(s):  
Carolina Flores-Muñoz ◽  
Francisca Garcia-Rojas ◽  
MIguel A. Perez ◽  
Odra Santander ◽  
Elena Mery ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
Hippocampal Neurons ◽  
Actin Polymerization ◽  
Adult Brain ◽  
Compensatory Mechanism ◽  
Compensatory Mechanisms ◽  
Pannexin 1 ◽  
Synapse Maintenance

Enhanced activity and overexpression of Pannexin 1 (PANX1) channels contribute to neuronal pathologies, such as epilepsy and Alzheimers disease (AD). In the hippocampus, the PANX1 channels ablation alters glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, PANX1-knockout (KO) mice still preserve the ability to learn, suggesting that compensatory mechanisms work to stabilize neuronal activity. Here, we show that the absence of PANX1 in the adult brain promotes a series of structural and functional modifications in KO hippocampal synapses, preserving spontaneous activity. Adult CA1 neurons of KO mice exhibit enhanced excitability, complex dendritic branching, spine maturation, and multiple synaptic contacts compared to the WT condition. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in actin polymerization and an imbalance between Rac1 and RhoA GTPase activity is observed in the absence of PANX1. Our findings highlight a novel interaction between PANX1, actin, and small Rho GTPases that appear to be relevant for synapse maintenance as a long-term compensatory mechanism for PANX1 deficiency.

Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases

2007 ◽  
Vol 120 (2) ◽  
pp. 279-288 ◽  
Author(s):  
A. Mendoza-Naranjo ◽  
C. Gonzalez-Billault ◽  
R. B. Maccioni
Keyword(s):  
Rho Gtpases ◽  
Hippocampal Neurons ◽  
Actin Polymerization

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.

scholarly journals The RhoGEF DOCK10 is essential for dendritic spine morphogenesis

2015 ◽  
Vol 26 (11) ◽  
pp. 2112-2127 ◽  
Author(s):  
Fanny Jaudon ◽  
Fabrice Raynaud ◽  
Rosine Wehrlé ◽  
Jean-Michel Bellanger ◽  
Mohamed Doulazmi ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Rho Gtpases ◽  
Hippocampal Neurons ◽  
Strong Increase ◽  
Molecular Signaling ◽  
Spine Density ◽  
Downstream Effectors ◽  
Postnatal Differentiation ◽  
Cytoskeleton Dynamics ◽  
Spine Morphogenesis

By regulating actin cytoskeleton dynamics, Rho GTPases and their activators RhoGEFs are implicated in various aspects of neuronal differentiation, including dendritogenesis and synaptogenesis. Purkinje cells (PCs) of the cerebellum, by developing spectacular dendrites covered with spines, represent an attractive model system in which to decipher the molecular signaling underlying these processes. To identify novel regulators of dendritic spine morphogenesis among members of the poorly characterized DOCK family of RhoGEFs, we performed gene expression profiling of fluorescence-activated cell sorting (FACS)-purified murine PCs at various stages of their postnatal differentiation. We found a strong increase in the expression of the Cdc42-specific GEF DOCK10. Depleting DOCK10 in organotypic cerebellar cultures resulted in dramatic dendritic spine defects in PCs. Accordingly, in mouse hippocampal neurons, depletion of DOCK10 or expression of a DOCK10 GEF-dead mutant led to a strong decrease in spine density and size. Conversely, overexpression of DOCK10 led to increased spine formation. We show that DOCK10 function in spinogenesis is mediated mainly by Cdc42 and its downstream effectors N-WASP and PAK3, although DOCK10 is also able to activate Rac1. Our global approach thus identifies an unprecedented function for DOCK10 as a novel regulator of dendritic spine morphogenesis via a Cdc42-mediated pathway.

scholarly journals Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons

2010 ◽  
Vol 109 (3) ◽  
pp. 804-819 ◽  
Author(s):  
Alfredo J. Garcia ◽  
Robert W. Putnam ◽  
Jay B. Dean
Keyword(s):  
Central Nervous System ◽  
Neural Plasticity ◽  
Hippocampal Neurons ◽  
Hippocampal Slice ◽  
Population Spike ◽  
Ca1 Neurons ◽  
Hyperbaric Hyperoxia ◽  
Diving Medicine ◽  
Population Spike Amplitude ◽  
Secondary Population

Breathing hyperbaric oxygen (HBO) is common practice in hyperbaric and diving medicine. The benefits of breathing HBO, however, are limited by the risk of central nervous system O2 toxicity, which presents as seizures. We tested the hypothesis that excitability increases in CA1 neurons of the rat hippocampal slice (400 μm) over a continuum of hyperoxia that spans normobaric and hyperbaric pressures. Amplitude changes of the orthodromic population spike were used to assess neuronal O2 sensitivity before, during, and following exposure to 0, 0.6, 0.95 (control), 2.84, and 4.54 atmospheres absolute (ATA) O2. Polarographic O2 electrodes were used to measure tissue slice Po2 (PtO2). In 0.95 ATA O2, core PtO2 at 200 μm deep was 115 ± 16 Torr (mean ± SE). Increasing O2 to 2.84 and 4.54 ATA increased core PtO2 to 1,222 ± 77 and 2,037 ± 157 Torr, respectively. HBO increased the orthodromic population spike amplitude and usually induced hyperexcitability (i.e., secondary population spikes) and, in addition, a long-lasting potentiation of the orthodromic population spike that we have termed “oxygen-induced potentiation” (OxIP). Exposure to 0.60 ATA O2 and hypoxia (0.00 ATA) decreased core PtO2 to 84 ± 6 and 20 ± 4 Torr, respectively, and abolished the orthodromic response. Reoxygenation from 0.0 or 0.6 ATA O2, however, usually produced a response similar to that of HBO: hyperexcitability and activation of OxIP. We conclude that CA1 neurons exhibit increased excitability and neural plasticity over a broad range of PtO2, which can be activated by a single, hyperoxic stimulus. We postulate that transient acute hyperoxia stimulus, whether caused by breathing HBO or reoxygenation following hypoxia (e.g., disordered breathing), is a powerful stimulant for orthodromic activity and neural plasticity in the CA1 hippocampus.

Distinct signals via Rho GTPases and Src drive shape changes by thrombin and sphingosine-1-phosphate in endothelial cells

2002 ◽  
Vol 115 (12) ◽  
pp. 2475-2484 ◽  
Author(s):  
Valérie Vouret-Craviari ◽  
Christine Bourcier ◽  
Etienne Boulter ◽  
Ellen Van Obberghen-Schilling
Keyword(s):  
Endothelial Cells ◽  
Rho Gtpases ◽  
Actin Polymerization ◽  
Morphological Changes ◽  
Umbilical Vein ◽  
Cell Spreading ◽  
Actin Binding ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Umbilical Vein Endothelial Cells

Soluble mediators such as thrombin and sphingosine-1-phosphate regulate morphological changes in endothelial cells that affect vascular permeability and new blood vessel formation. Although these ligands activate a similar set of heterotrimeric G proteins, thrombin causes cell contraction and rounding whereas sphingosine-1-phosphate induces cell spreading and migration. A functional requirement for Rho family GTPases in the cytoskeletal responses to both ligands has been established, yet the dynamics of their regulation and additional signaling mechanisms that lead to such opposite effects remain poorly understood. Using a pull-down assay to monitor the activity of Rho GTPases in human umbilical vein endothelial cells, we find significant temporal and quantitative differences in RhoA and Rac1 activation. High levels of active RhoA rapidly accumulate in cells in response to thrombin whereas Rac1 is inhibited. In contrast, sphingosine-1-phosphate addition leads to comparatively weak and delayed activation of RhoA and it activates Rac1. In addition, we show here that sphingosine-1-phosphate treatment activates a Src family kinase and triggers recruitment of the F-actin-binding protein cortactin to sites of actin polymerization at the rim of membrane ruffles. Both Src and Rac pathways are essential for lamellipodia targeting of cortactin. Further, Src plays a determinant role in sphingosine-1-phosphate-induced cell spreading and migration. Taken together these data demonstrate that the thrombin-induced contractile and immobile phenotype in endothelial cells reflects both robust RhoA activation and Rac inhibition, whereas Src- and Rac-dependent events couple sphingosine-1-phosphate receptors to the actin polymerizing machinery that drives the extension of lamellipodia and cell migration.

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