scholarly journals Semaphorin4D induces inhibitory synapse formation by rapid stabilization of presynaptic boutons via MET co-activation

2017 ◽  
Author(s):  
Cátia P. Frias ◽  
Tom Bresser ◽  
Lisa Scheefhals ◽  
Hai Yin Hu ◽  
Paul M. P. van Bergen en Henegouwen ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Synapse Formation ◽  
Inhibitory Synapse ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Signaling Cascade ◽  
Molecular Processes ◽  
Intracellular Signaling Cascade ◽  
Gabaergic Synapses ◽  
Presynaptic Boutons

ABSTRACTChanges in inhibitory connections are essential for experience-dependent circuit adaptations. Defects in inhibitory synapses are linked to neurodevelopmental disorders, but the molecular processes underlying inhibitory synapse formation are not well understood. Here we use high resolution two-photon microscopy in organotypic hippocampal slices to examine the signaling pathways induced by the postsynaptic signaling molecule Semaphorin4D (Sema4D) during inhibitory synapse formation. By monitoring changes in individual GFP-labeled presynaptic boutons we found that the primary action of Sema4D is to induce stabilization of presynaptic boutons within tens of minutes. Stabilizing boutons rapidly recruited synaptic vesicles, which was followed by accumulation of postsynaptic gephyrin. Newly formed inhibitory synapses were complete and functional after 24 hours, as determined by electrophysiology and immunohistochemistry. We further showed that Sema4D signaling is regulated by network activity and can induce a local increase in bouton density, suggesting a possible role in circuit adaptation. We further examined the intracellular signaling cascade triggered by Sema4D and found that bouton stabilization occurred through rapid remodeling of actin, and this could be mimicked by the actin-depolymerizing drug Latrunculin B or by reducing ROCK activity. The intracellular signaling cascade required activation of the receptor tyrosine kinase MET, which is a well-known autism risk factor. Our immunohistochemistry data suggests that MET may be localized to presynaptic inhibitory axons. Together, our data yield important insights in the molecular pathway underlying activity-dependent Sema4D-induced synapse formation and reveal a novel role for MET in inhibitory synapses.Significance StatementGABAergic synapses provide the main inhibitory control of neuronal activity in the brain. We make important steps in unraveling the molecular processes that take place when formation of inhibitory synapses is triggered by a specific signaling molecule, Sema4D. We find that this process depends on network activity and involves specific remodeling of the intracellular actin cytoskeleton. We also reveal a previously unknown role for MET in inhibitory synapses. As defects in GABAergic synapses have been implied in many brain disorders, and mutations in MET are strong risk factors for autism, our findings urge for a further investigation of the role of MET at inhibitory synapses.

The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽  
2021 ◽  
pp. 273250162110243
Author(s):  
Mikhail Pakvasa ◽  
Andrew B. Tucker ◽  
Timothy Shen ◽  
Tong-Chuan He ◽  
Russell R. Reid
Keyword(s):  
Intracellular Signaling ◽  
Limb Development ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Craniofacial Development ◽  
Signaling Cascade ◽  
Signaling Mechanisms ◽  
Intracellular Signaling Cascade ◽  
And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

scholarly journals Trophic Factor-Induced Plasticity of Synaptic Connections Between Identified Lymnaea Neurons

1999 ◽  
Vol 6 (3) ◽  
pp. 307-316 ◽  
Author(s):  
Melanie A. Woodin ◽  
Toshiro Hamakawa ◽  
Mayumi Takasaki ◽  
Ken Lukowiak ◽  
Naweed I. Syed
Keyword(s):  
Tyrosine Kinases ◽  
Synapse Formation ◽  
Initial Period ◽  
Defined Medium ◽  
Inhibitory Synapse ◽  
Trophic Factors ◽  
Trophic Factor ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synaptic Connections

Neurotrophic factors participate in both developmental and adult synaptic plasticity; however, the underlying mechanisms remain unknown. Using soma–soma synapses between the identified Lymnaea neurons, we demonstrate that the brain conditioned medium (CM)-derived trophic factors are required for the formation of excitatory but not the inhibitory synapse. Specifically, identified presynaptic [right pedal dorsal 1 (RPeD1) and visceral dorsal 4 (VD4)] and postsynaptic [visceral dorsal 2/3 (VD2/3) and left pedal dorsal 1 (LPeD1)] neurons were soma–soma paired either in the absence or presence of CM. We show that in defined medium (DM—does not contain extrinsic trophic factors), appropriate excitatory synapses failed to develop between RPeD1 and VD2/3. Instead, inappropriate inhibitory synapses formed between VD2/3 and RPeD1. Similarly, mutual inhibitory synapses developed between VD4 and LPeD1 in DM. These inhibitory synapses were termed novel because they do not exist in the intact brain. To test whether DM-induced, inappropriate inhibitory synapses could be corrected by the addition of CM, cells were first paired in DM for an initial period of 12 hr. DM was then replaced with CM, and simultaneous intracellular recordings were made from paired cells after 6–12 hr of CM substitution. Not only did CM induce the formation of appropriate excitatory synapses between both cell pairs, but it also reduced the incidence of inappropriate inhibitory synapse formation. The CM-induced plasticity of synaptic connections involved new protein synthesis and transcription and was mediated via receptor tyrosine kinases. Taken together, our data provide the first direct insight into the cellular mechanism underlying trophic factor-induced specificity and plasticity of synaptic connections between soma–soma paired Lymnaea neurons.

scholarly journals Possible regulation of genes associated with intracellular signaling cascade in rat liver regeneration

2009 ◽  
Vol 44 (4) ◽  
pp. 462-470 ◽  
Author(s):  
Cun-Shuan Xu ◽  
Heng-Yi Shao ◽  
Shuai-Shuai Liu ◽  
Bo Qin ◽  
Xiu-Feng Sun ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Rat Liver ◽  
Intracellular Signaling ◽  
Signaling Cascade ◽  
Rat Liver Regeneration ◽  
Intracellular Signaling Cascade

scholarly journals Inhibitory control in neuronal networks relies on the extracellular matrix integrity

2021 ◽  
Author(s):  
Egor Dzyubenko ◽  
Michael Fleischer ◽  
Daniel Manrique-Castano ◽  
Mina Borbor ◽  
Christoph Kleinschnitz ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Inhibitory Control ◽  
Neuronal Networks ◽  
Synaptic Strength ◽  
Inhibitory Synapse ◽  
Receptor Expression ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Neuronal Network Activity ◽  
Synapse Density

AbstractInhibitory control is essential for the regulation of neuronal network activity, where excitatory and inhibitory synapses can act synergistically, reciprocally, and antagonistically. Sustained excitation-inhibition (E-I) balance, therefore, relies on the orchestrated adjustment of excitatory and inhibitory synaptic strength. While growing evidence indicates that the brain’s extracellular matrix (ECM) is a crucial regulator of excitatory synapse plasticity, it remains unclear whether and how the ECM contributes to inhibitory control in neuronal networks. Here we studied the simultaneous changes in excitatory and inhibitory connectivity after ECM depletion. We demonstrate that the ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Quantification of synapses and super-resolution microscopy showed that depletion of the ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. The reduction of inhibitory synapse density is partially compensated by the homeostatically increasing synaptic strength via the reduction of presynaptic GABAB receptors, as indicated by patch-clamp measurements and GABAB receptor expression quantifications. However, both spiking and bursting activity in neuronal networks is increased after ECM depletion, as indicated by multi-electrode recordings. With computational modelling, we determined that ECM depletion reduces the inhibitory connectivity to an extent that the inhibitory synapse scaling does not fully compensate for the reduced inhibitory synapse density. Our results indicate that the brain’s ECM preserves the balanced state of neuronal networks by supporting inhibitory control via inhibitory synapse stabilization, which expands the current understanding of brain activity regulation. Graphic abstract

scholarly journals Hyaluronan regulates synapse formation and function in developing neural networks

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emily Wilson ◽  
Warren Knudson ◽  
Karen Newell-Litwa
Keyword(s):  
Extracellular Matrix ◽  
Brain Development ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Inhibitory Synapse ◽  
Synaptic Function ◽  
Excitatory Synapse ◽  
Network Activity ◽  
Excitatory Synapses ◽  
Inhibitory Signaling

Abstract Neurodevelopmental disorders present with synaptic alterations that disrupt the balance between excitatory and inhibitory signaling. For example, hyperexcitability of cortical neurons is associated with both epilepsy and autism spectrum disorders. However, the mechanisms that initially establish the balance between excitatory and inhibitory signaling in brain development are not well understood. Here, we sought to determine how the extracellular matrix directs synapse formation and regulates synaptic function in a model of human cortical brain development. The extracellular matrix, making up twenty percent of brain volume, is largely comprised of hyaluronan. Hyaluronan acts as both a scaffold of the extracellular matrix and a space-filling molecule. Hyaluronan is present from the onset of brain development, beginning with neural crest cell migration. Through acute perturbation of hyaluronan levels during synaptogenesis, we sought to determine how hyaluronan impacts the ratio of excitatory to inhibitory synapse formation and the resulting neural activity. We used 3-D cortical spheroids derived from human induced pluripotent stem cells to replicate this neurodevelopmental window. Our results demonstrate that hyaluronan preferentially surrounds nascent excitatory synapses. Removal of hyaluronan increases the expression of excitatory synapse markers and results in a corresponding increase in the formation of excitatory synapses, while also decreasing inhibitory synapse formation. This increased excitatory synapse formation elevates network activity, as demonstrated by microelectrode array analysis. In contrast, the addition of purified hyaluronan suppresses excitatory synapse formation. These results establish that the hyaluronan extracellular matrix surrounds developing excitatory synapses, where it critically regulates synapse formation and the resulting balance between excitatory to inhibitory signaling.

scholarly journals IL-4 induces a wide-spectrum intracellular signaling cascade in CD8+T cells

2007 ◽  
Vol 81 (4) ◽  
pp. 1102-1110 ◽  
Author(s):  
Ana Acacia de Sa Pinheiro ◽  
Alexandre Morrot ◽  
Sumana Chakravarty ◽  
Michael Overstreet ◽  
Jay H. Bream ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Intracellular Signaling ◽  
Wide Spectrum ◽  
Signaling Cascade ◽  
Intracellular Signaling Cascade

scholarly journals The Complicated Body in Motion: Rediscovering the Mechanical Stimulations in Cell Models of Human Disease

2019 ◽  
Author(s):  
Tzyy-Yue Wong ◽  
Yu-Kai Tseng ◽  
Tung-Chen Yeh ◽  
Rong-Chang Jhong ◽  
Yue-Fang Wang ◽  
...  
Keyword(s):  
Mechanical Stimulation ◽  
Intracellular Signaling ◽  
The Body ◽  
Signaling Cascade ◽  
Physical Injury ◽  
Cell Models ◽  
Physical Stimulation ◽  
Intracellular Signaling Cascade ◽  
The Mind

Thought runs through the mind like blood runs through our body to keep us alive. Like the mind, the body does not stay inert and is in constant motion. Not a single cell in our body is left inert unless cell is under stress or dying. These scenarios are reflected upon when a person is sick, the person lies in bed with less movement; however, is active when the person is healthy. The topic of mechanical stimulation has emerged due to the increasing understanding of the physical stimulations we face each day. Further understanding of the mechanically-regulated mechanism can help us explore the pathological events in a disease. Here, we reviewed the role of sensory proteins in pathological events that are observed in cardiomyopathy, cancer, respiratory, renal, obesity, genetics, physical injury and bacterial infection. Taken together, sensory proteins are mechanically-activated which assist reception of external physical stimulation and convert into biochemical to trigger intracellular signaling cascade.

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