scholarly journals The Involvement of Neuron-Specific Factors in Dendritic Spinogenesis: Molecular Regulation and Association with Neurological Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Hsiao-Tang Hu ◽  
Pu-Yun Shih ◽  
Yu-Tzu Shih ◽  
Yi-Ping Hsueh
Keyword(s):  
Actin Cytoskeleton ◽  
Dendritic Spine ◽  
Neurological Disorders ◽  
Synapse Formation ◽  
Adaptor Proteins ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Excitatory Synapses ◽  
Specific Factors ◽  
And Function

Dendritic spines are the location of excitatory synapses in the mammalian nervous system and are neuron-specific subcellular structures essential for neural circuitry and function. Dendritic spine morphology is determined by the F-actin cytoskeleton. F-actin remodeling must coordinate with different stages of dendritic spinogenesis, starting from dendritic filopodia formation to the filopodia-spines transition and dendritic spine maturation and maintenance. Hundreds of genes, including F-actin cytoskeleton regulators, membrane proteins, adaptor proteins, and signaling molecules, are known to be involved in regulating synapse formation. Many of these genes are not neuron-specific, but how they specifically control dendritic spine formation in neurons is an intriguing question. Here, we summarize how ubiquitously expressed genes, including syndecan-2, NF1 (encoding neurofibromin protein), VCP, and CASK, and the neuron-specific gene CTTNBP2 coordinate with neurotransmission, transsynaptic signaling, and cytoskeleton rearrangement to control dendritic filopodia formation, filopodia-spines transition, and dendritic spine maturation and maintenance. The aforementioned genes have been associated with neurological disorders, such as autism spectrum disorders (ASDs), mental retardation, learning difficulty, and frontotemporal dementia. We also summarize the corresponding disorders in this report.

scholarly journals An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum

2021 ◽  
Vol 15 ◽  
Author(s):  
Esther Suk King Lai ◽  
Hisako Nakayama ◽  
Taisuke Miyazaki ◽  
Takanobu Nakazawa ◽  
Katsuhiko Tabuchi ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Synapse Formation ◽  
Single Point ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Single Point Mutation ◽  
Synapse Elimination ◽  
Wild Type ◽  
Post Mortem Brain ◽  
And Function

Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10–15 (P10–15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.

scholarly journals BDNF signaling during the lifetime of dendritic spines

2020 ◽  
Vol 382 (1) ◽  
pp. 185-199 ◽  
Author(s):  
Marta Zagrebelsky ◽  
Charlotte Tacke ◽  
Martin Korte
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Neurological Disorders ◽  
Current Knowledge ◽  
Conclusive Evidence ◽  
Excitatory Synapses ◽  
Neuronal Homeostasis ◽  
Bdnf Signaling ◽  
Spine Number

Abstract Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

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 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 Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant

2021 ◽  
Vol 12 ◽  
Author(s):  
Justyna Paprocka ◽  
Szymon Ziętkiewicz ◽  
Joanna Kosińska ◽  
Ewa Kaczorowska ◽  
Rafał Płoski
Keyword(s):  
Protein Interactions ◽  
De Novo ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Excitatory Synapses ◽  
Scaffolding Proteins ◽  
Protein Protein Interactions ◽  
Disease Associations ◽  
Dynamics Simulations ◽  
And Function

The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and epilepsy, whereas relatively little is known about disease associations of SHANK1. Here, we propose a novel de novo mosaic p.(Gly126Arg) SHANK1 variant as the monogenic cause of disease in a patient who presented, from the age of 2 years, moderate intellectual disability, autism, and refractory epilepsy of the Lennox–Gastaut type. The epilepsy responded remarkably well to cannabidiol add-on therapy. In silico analyses including homology modeling and molecular dynamics simulations indicated the deleterious effect of SHANK1 p.(Gly126Arg) on the protein structure and the related function associated with protein–protein interactions. In particular, the variant was predicted to disrupt a hitherto unknown conserved region of SHANK1 protein with high homology to a recently recognized functionally relevant domain in SHANK3 implicated in ligand binding, including the “non-canonical” binding of Rap1.

scholarly journals Glypicans and Heparan Sulfate in Synaptic Development, Neural Plasticity, and Neurological Disorders

2021 ◽  
Vol 15 ◽  
Author(s):  
Keisuke Kamimura ◽  
Nobuaki Maeda
Keyword(s):  
Heparan Sulfate ◽  
Neural Plasticity ◽  
Neurological Disorders ◽  
Network Formation ◽  
Synapse Formation ◽  
Protein Tyrosine Phosphatases ◽  
Autism Spectrum ◽  
Bmp Signaling ◽  
Receptor Protein ◽  
Core Proteins

Heparan sulfate proteoglycans (HSPGs) are components of the cell surface and extracellular matrix, which bear long polysaccharides called heparan sulfate (HS) attached to the core proteins. HSPGs interact with a variety of ligand proteins through the HS chains, and mutations in HSPG-related genes influence many biological processes and cause various diseases. In particular, recent findings from vertebrate and invertebrate studies have raised the importance of glycosylphosphatidylinositol-anchored HSPGs, glypicans, as central players in the development and functions of synapses. Glypicans are important components of the synapse-organizing protein complexes and serve as ligands for leucine-rich repeat transmembrane neuronal proteins (LRRTMs), leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatases (RPTPs), and G-protein-coupled receptor 158 (GPR158), regulating synapse formation. Many of these interactions are mediated by the HS chains of glypicans. Neurexins (Nrxs) are also synthesized as HSPGs and bind to some ligands in common with glypicans through HS chains. Therefore, glypicans and Nrxs may act competitively at the synapses. Furthermore, glypicans regulate the postsynaptic expression levels of ionotropic glutamate receptors, controlling the electrophysiological properties and non-canonical BMP signaling of synapses. Dysfunctions of glypicans lead to failures in neuronal network formation, malfunction of synapses, and abnormal behaviors that are characteristic of neurodevelopmental disorders. Recent human genetics revealed that glypicans and HS are associated with autism spectrum disorder, neuroticism, and schizophrenia. In this review, we introduce the studies showing the roles of glypicans and HS in synapse formation, neural plasticity, and neurological disorders, especially focusing on the mouse and Drosophila as potential models for human diseases.

scholarly journals Kalirin-7 is a Key Player in the Formation of Excitatory Synapses in Hippocampal Neurons

2010 ◽  
Vol 10 ◽  
pp. 1655-1666 ◽  
Author(s):  
Xin-Ming Ma
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Synapse Formation ◽  
Pdz Domain ◽  
Long Term Potentiation ◽  
Binding Motif ◽  
Excitatory Synapses ◽  
Spine Density ◽  
Chronic Cocaine ◽  
And Function

Kalirin-7 (Kal7), a major isoform of Kalirin in the adult rodent hippocampus, is exclusively localized to the postsynaptic side of mature excitatory synapses in hippocampal neurons. Kal7 interacts with multiple PDZ domain—containing proteins through its unique PDZ binding motif. Overexpression of Kal7 increases spine density and spine size, whereas reduction of endogenous Kal7 expression by small hairpin RNA (shRNA) causes a decrease in synapse number and spine density in cultured hippocampal neurons. Hippocampal CA1 pyramidal neurons of Kal7 knockout (Kal7KO) mice show decreased spine density, spine length, synapse number, and postsynaptic density (PSD) size in their apical dendrites; are deficient in long-term potentiation (LTP); and exhibit decreased frequency of spontaneous excitatory postsynaptic current (sEPSC). Kal7 plays a key role in estrogen-mediated spine/synapse formation in hippocampal neurons. Kal7 is also an essential determinant of dendritic spine formation following chronic cocaine treatment. Kal7 plays a key role in excitatory synapse formation and function.

scholarly journals Human SYNGAP1 Regulates the Development of Neuronal Activity by Controlling Dendritic and Synaptic Maturation

2020 ◽  
Author(s):  
Nerea Llamosas ◽  
Vineet Arora ◽  
Ridhima Vij ◽  
Murat Kilinc ◽  
Lukasz Bijoch ◽  
...  
Keyword(s):  
Protein Expression ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Global Developmental Delay ◽  
Excitatory Synapses ◽  
Loss Of Function ◽  
Biological Studies ◽  
Human Neurons ◽  
And Function

AbstractSYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder defined by cognitive impairment, social-communication disorder, and early-onset seizures. Cell biological studies in mouse and rat neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, with loss-of-function variants driving formation of larger dendritic spines and stronger glutamatergic transmission. However, studies to date have been limited to mouse and rat neurons. Therefore, it remains unknown how SYNGAP1 loss-of-function impacts the development and function of human neurons. To address this, we employed CRISPR/Cas9 technology to ablate SYNGAP1 protein expression in neurons derived from a human induced pluripotent stem cell line (hiPSC). Reducing SynGAP protein expression in developing hiPSC-derived neurons enhanced dendritic morphogenesis, leading to larger neurons compared to those derived from isogenic controls. Consistent with larger dendritic fields, we also observed a greater number of morphologically defined excitatory synapses in cultures containing these neurons. Moreover, neurons with reduced SynGAP protein had stronger excitatory synapses and expressed synaptic activity earlier in development. Finally, distributed network spiking activity appeared earlier, was substantially elevated, and exhibited greater bursting behavior in SYNGAP1 null neurons. We conclude that SYNGAP1 regulates the postmitotic maturation of human neurons made from hiPSCs, which influences how activity develops within nascent neural networks. Alterations to this fundamental neurodevelopmental process may contribute to the etiology of SYNGAP1-related disorders.

scholarly journals The Interplay between Synaptic Activity and Neuroligin Function in the CNS

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Xiaoge Hu ◽  
Jian-hong Luo ◽  
Junyu Xu
Keyword(s):  
Synapse Formation ◽  
Autism Spectrum ◽  
Synaptic Activity ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Spectrum Disorders ◽  
Cell Adhesion Proteins ◽  
The Relationship

Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previousin vitroandin vivostudies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.

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