scholarly journals ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bin Luo ◽  
Ziyang Liu ◽  
Dong Lin ◽  
Wenbing Chen ◽  
Dongyan Ren ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Pyramidal Neurons ◽  
Synapse Formation ◽  
Inhibitory Synapse ◽  
Inhibitory Synapses ◽  
Independent Manner ◽  
Precise Control

AbstractThe precise control of the nervous system function under the vitality of synapses is extremely critical. Efforts have been taken to explore the underlying cellular and molecular mechanisms for synapse formation. Cell adhesion molecules have been found important for synapse assembly in the brain. Many trans-adhesion complexes have been identified to modulate excitatory synapse formation. However, little is known about the synaptogenic mechanisms for inhibitory synapses. ErbB4 is a receptor tyrosine kinase enriched in interneurons. Here, we showed that overexpressing ErbB4 in HEK293T cells induced gephyrin or GABAAR α1 puncta in co-cultured primary hippocampal neurons. This induction of ErbB4 was independent of its kinase activity. K751M, a kinase-dead mutant of ErbB4, can also induce gephyrin or GABAAR α1 puncta in the co-culture system. We further constructed K751M knock-in mice and found that the homozygous were viable at birth and fertile without changes in gross brain structure. The number of interneurons and inhibitory synapses onto pyramidal neurons (PyNs) were comparable between K751M and wild-type mice but decreased in ErbB4-Null mice. Moreover, ErbB4 can interact in trans with Slitrk3, a transmembrane postsynaptic protein at inhibitory synapses, through the extracellular RLD domain of ErbB4. The deletion of RLD diminished the induction of gephyrin or GABAAR α1 puncta by ErbB4. Finally, disruption of ErbB4–Slitrk3 interaction through neutralization of Slitrk3 by secretable RLD decreased inhibitory synapses onto PyNs and impaired GABAergic transmission. These results identify that ErbB4, as a cell adhesion molecule, promotes inhibitory synapse formation onto PyNs by interacting with Slitrk3 and in a kinase-independent manner, providing an unexpected mechanism of ErbB4 in inhibitory synapse formation.

scholarly journals BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin–β-catenin interactions

2006 ◽  
Vol 174 (2) ◽  
pp. 289-299 ◽  
Author(s):  
Shernaz X. Bamji ◽  
Beatriz Rico ◽  
Nikole Kimes ◽  
Louis F. Reichardt
Keyword(s):  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Time Lapse ◽  
Synapse Density ◽  
Vesicle Mobility ◽  
Small Clusters ◽  
Vertebrate Central Nervous System

Neurons of the vertebrate central nervous system have the capacity to modify synapse number, morphology, and efficacy in response to activity. Some of these functions can be attributed to activity-induced synthesis and secretion of the neurotrophin brain-derived neurotrophic factor (BDNF); however, the molecular mechanisms by which BDNF mediates these events are still not well understood. Using time-lapse confocal analysis, we show that BDNF mobilizes synaptic vesicles at existing synapses, resulting in small clusters of synaptic vesicles “splitting” away from synaptic sites. We demonstrate that BDNF's ability to mobilize synaptic vesicle clusters depends on the dissociation of cadherin–β-catenin adhesion complexes that occurs after tyrosine phosphorylation of β-catenin. Artificially maintaining cadherin–β-catenin complexes in the presence of BDNF abolishes the BDNF-mediated enhancement of synaptic vesicle mobility, as well as the longer-term BDNF-mediated increase in synapse number. Together, this data demonstrates that the disruption of cadherin–β-catenin complexes is an important molecular event through which BDNF increases synapse density in cultured hippocampal neurons.

scholarly journals Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development

2013 ◽  
Vol 200 (3) ◽  
pp. 321-336 ◽  
Author(s):  
Katherine L. Pettem ◽  
Daisaku Yokomaku ◽  
Hideto Takahashi ◽  
Yuan Ge ◽  
Ann Marie Craig
Keyword(s):  
Neurodevelopmental Disorders ◽  
Hippocampal Neurons ◽  
Rare Variants ◽  
Inhibitory Synapse ◽  
Excitatory Synapse ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synapse Development ◽  
Multiple Protein ◽  
Synapse Density

Rare variants in MDGAs (MAM domain–containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse–organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin–neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.

scholarly journals The Cell Adhesion Molecule Neurofascin Stabilizes Axo-axonic GABAergic Terminals at the Axon Initial Segment

2011 ◽  
Vol 286 (27) ◽  
pp. 24385-24393 ◽  
Author(s):  
Martin Kriebel ◽  
Jennifer Metzger ◽  
Sabine Trinks ◽  
Deepti Chugh ◽  
Robert J. Harvey ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Cell Adhesion Molecule ◽  
Synapse Formation ◽  
Growth Factor Receptor ◽  
Axon Initial Segment ◽  
Adult Rat ◽  
Receptor Clusters

Cell adhesion molecules regulate synapse formation and maintenance via transsynaptic contact stabilization involving both extracellular interactions and intracellular postsynaptic scaffold assembly. The cell adhesion molecule neurofascin is localized at the axon initial segment of granular cells in rat dentate gyrus, which is mainly targeted by chandelier cells. Lentiviral shRNA-mediated knockdown of neurofascin in adult rat brain indicates that neurofascin regulates the number and size of postsynaptic gephyrin scaffolds, the number of GABAA receptor clusters as well as presynaptic glutamate decarboxylase-positive terminals at the axon initial segment. By contrast, overexpression of neurofascin in hippocampal neurons increases gephyrin cluster size presumably via stimulation of fibroblast growth factor receptor 1 signaling pathways.

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.

Plexin-B3 suppresses excitatory and promotes inhibitory synapse formation in rat hippocampal neurons

2015 ◽  
Vol 335 (2) ◽  
pp. 269-278 ◽  
Author(s):  
Piret Laht ◽  
Epp Tammaru ◽  
Maarja Otsus ◽  
Johan Rohtla ◽  
Liivi Tiismus ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Inhibitory Synapse

scholarly journals MuSK induces in vivo acetylcholine receptor clusters in a ligand-independent manner

2001 ◽  
Vol 155 (7) ◽  
pp. 1287-1296 ◽  
Author(s):  
Andreas Sander ◽  
Boris A. Hesser ◽  
Veit Witzemann
Keyword(s):  
Acetylcholine Receptor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Synapse Formation ◽  
Kinase Domain ◽  
Direct Gene Transfer ◽  
Independent Manner ◽  
Direct Gene ◽  
Receptor Clusters

Muscle-specific receptor tyrosine kinase (MuSK) is required for the formation of the neuromuscular junction. Using direct gene transfer into single fibers, MuSK was expressed extrasynaptically in innervated rat muscle in vivo to identify its contribution to synapse formation. Spontaneous MuSK kinase activity leads, in the absence of its putative ligand neural agrin, to the appearance of ϵ-subunit–specific transcripts, the formation of acetylcholine receptor clusters, and acetylcholinesterase aggregates. Expression of kinase-inactive MuSK did not result in the formation of acetylcholine receptor (AChR) clusters, whereas a mutant MuSK lacking the ectodomain did induce AChR clusters. The contribution of endogenous MuSK was excluded by using genetically altered mice, where the kinase domain of the MuSK gene was flanked by loxP sequences and could be deleted upon expression of Cre recombinase. This allowed the conditional inactivation of endogenous MuSK in single muscle fibers and prevented the induction of ectopic AChR clusters. Thus, the kinase activity of MuSK initiates signals that are sufficient to induce the formation of AChR clusters. This process does not require additional determinants located in the ectodomain.

scholarly journals The EphA8 Receptor Regulates Integrin Activity through p110γ Phosphatidylinositol-3 Kinase in a Tyrosine Kinase Activity-Independent Manner

2001 ◽  
Vol 21 (14) ◽  
pp. 4579-4597 ◽  
Author(s):  
Changkyu Gu ◽  
Soochul Park
Keyword(s):  
Cell Adhesion ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Cell Attachment ◽  
Hek293 Cells ◽  
Stable Complex ◽  
Phosphatidylinositol 3 Kinase ◽  
Independent Manner ◽  
Phosphatidylinositol 3

ABSTRACT Recent genetic studies suggest that ephrins may function in a kinase-independent Eph receptor pathway. Here we report that expression of EphA8 in either NIH 3T3 or HEK293 cells enhanced cell adhesion to fibronectin via α5β1- or β3integrins. Interestingly, a kinase-inactive EphA8 mutant also markedly promoted cell attachment to fibronectin in these cell lines. Using a panel of EphA8 point mutants, we have demonstrated that EphA8 kinase activity does not correlate with its ability to promote cell attachment to fibronectin. Analysis using EphA8 extracellular and intracellular domain mutants has revealed that enhanced cell adhesion is dependent on ephrin A binding to the extracellular domain and the juxtamembrane segment of the cytoplasmic domain of the receptor. EphA8-promoted adhesion was efficiently inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor. Additionally, we found that EphA8 had associated PI 3-kinase activity and that the p110γ isoform of PI 3-kinase is associated with EphA8. In vitro binding experiments revealed that the EphA8 juxtamembrane segment was sufficient for the formation of a stable complex with p110γ. Similar results were obtained in assay using cells stripped of endogenous ephrin A ligands by treatment with preclustered ephrin A5-Fc proteins. In addition, a membrane-targeted lipid kinase-inactive p110γ mutant was demonstrated to stably associate with EphA8 and suppress EphA8-promoted cell adhesion to fibronectin. Taken together, these results suggest the presence of a novel mechanism by which the EphA8 receptor localizes p110γ PI 3-kinase to the plasma membrane in a tyrosine kinase-independent fashion, thereby allowing access to lipid substrates to enable the signals required for integrin-mediated cell adhesion.

scholarly journals Ras induces anchorage-independent growth by subverting multiple adhesion-regulated cell cycle events.

1996 ◽  
Vol 16 (7) ◽  
pp. 3370-3380 ◽  
Author(s):  
J S Kang ◽  
R S Krauss
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Cyclin E ◽  
Ectopic Expression ◽  
Cyclin A ◽  
Semisolid Medium ◽  
Anchorage Independent Growth

Anchorage-independent growth is a hallmark of transformed cells, but little is known of the molecular mechanisms that underlie this phenomenon. We describe here studies of cell cycle control of anchorage-independent growth induced by the ras oncogene, with the use of a somatic cell mutant fibroblast line (ER-1-2) that is specifically defective in oncogene-mediated, anchorage-independent growth. Control, nontransformed PKC3-F4 cells and ER-1-2 cells cannot proliferate in semisolid medium. Three important cell cycle events are dependent on adhesion of these cells to a substratum: phosphorylation of the retinoblastoma protein, pRB; cyclin E-dependent kinase activity; and cyclin A expression. PKC3-F4 cells that express ras (PKC3-F4/ras cells) proliferate in nonadherent cultures, and each of these three events occurs in the absence of adhesion in PKC3-F4/ras cells. Thus, ras can override the adhesion requirement of cellular functions that are necessary for cell cycle progression. ER-1-2 cells that express ras (ER-1-2/ras cells) possess hyperphosphorylated forms of pRB and cyclin E-dependent kinase activity in the absence of adhesion but remain adhesion dependent for expression of cyclin A. The adhesion dependence of pRB phosphorylation and cyclin E-dependent kinase activity is therefore dissociable from the adhesion dependence of cyclin A expression. Furthermore, ectopic expression of cyclin A is sufficient to rescue anchorage-independent growth of ER-1-2/ras cells but does not induce anchorage-independent growth of PKC3-F4 or ER-1-2 cells. However, like pRB phosphorylation and cyclin E-dependent kinase activity, the kinase activity associated with ectopically expressed cyclin A is dependent on cell adhesion, and this dependence is overcome by ras. Thus, the induction of anchorage-independent growth by ras may involve multiple signals that lead to both expression of cyclin A and activation of G1 cyclin-dependent kinase activities in the absence of cell adhesion.

scholarly journals Stem cell models of human synapse development and degeneration

2018 ◽  
Vol 29 (24) ◽  
pp. 2913-2921 ◽  
Author(s):  
Emily S. Wilson ◽  
Karen Newell-Litwa
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Synaptic Activity ◽  
Inhibitory Synapses ◽  
Synapse Development ◽  
Synapse Loss ◽  
Brain Models ◽  
Induced Pluripotent ◽  
Stem Cell Models ◽  
Neuronal Disorders

Many brain disorders exhibit altered synapse formation in development or synapse loss with age. To understand the complexities of human synapse development and degeneration, scientists now engineer neurons and brain organoids from human-induced pluripotent stem cells (hIPSC). These hIPSC-derived brain models develop both excitatory and inhibitory synapses and functional synaptic activity. In this review, we address the ability of hIPSC-derived brain models to recapitulate synapse development and insights gained into the molecular mechanisms underlying synaptic alterations in neuronal disorders. We also discuss the potential for more accurate human brain models to advance our understanding of synapse development, degeneration, and therapeutic responses.

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