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 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 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 Hyperexcitability and loss of feedforward inhibition in the Fmr1KO lateral amygdala

2020 ◽  
Author(s):  
E. Mae Guthman ◽  
Matthew N. Svalina ◽  
Christian A. Cea-Del Rio ◽  
J. Keenan Kushner ◽  
Serapio M. Baca ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Excitatory Synapses ◽  
Lateral Amygdala ◽  
Early Postnatal Development ◽  
Whole Cell Patch Clamp ◽  
Patch Clamp Electrophysiology

SummaryFragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorders (ASDs), and anxiety disorders. The disruption in the function of the FMR1 gene results in a range of alterations in cellular and synaptic function. Previous studies have identified dynamic alterations in inhibitory neurotransmission in early postnatal development in the amygdala of the mouse model of FXS. Yet little is known how these changes alter microcircuit development and plasticity in the lateral amygdala (LA). Using whole-cell patch clamp electrophysiology, we demonstrate that principal neurons (PNs) in the LA exhibit hyperexcitability with a concomitant increase in the synaptic strength of excitatory synapses in the BLA. Further, reduced feed-forward inhibition appears to enhance synaptic plasticity in the FXS amygdala. These results demonstrate that plasticity is enhanced in the amygdala of the juvenile Fmr1 KO mouse and that E/I imbalance may underpin anxiety disorders commonly seen in FXS and ASDs.

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 FMRP regulates experience-dependent maturation of callosal synaptic connections and bilateral cortical synchrony

2021 ◽  
Author(s):  
Zhe Zhang ◽  
Jeffrey Rumschlag ◽  
Carrie R Jonak ◽  
Devin K Binder ◽  
Khaleel A Razak ◽  
...  
Keyword(s):  
Fragile X ◽  
Sensory Deprivation ◽  
Sensory Stimulation ◽  
Brain Dysfunction ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Excitatory Synapses ◽  
Loss Of Function ◽  
Interhemispheric Connectivity ◽  
Eeg Recordings

Reduced structural and functional interhemispheric connectivity correlates with the severity Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated synaptic function, indicative of increased 'silent', or immature, callosal synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in promoting callosal synaptic connectivity. Multielectrode EEG recordings in awake Fmr1 KO mice find reduced coherence of bilateral neural oscillations in beta and gamma frequencies during rest and sensory stimulation, reflecting reduced interhemispheric integration. Our findings reveal the cellular and synaptic mechanisms by which loss of Fmr1 leads to reduced interhemispheric connectivity and suggests a novel biomarker of brain dysfunction in FXS.

scholarly journals Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

2021 ◽  
Author(s):  
Megha Amar ◽  
Akula Bala Pramod ◽  
Nam-Kyung Yu ◽  
Victor Munive Herrera ◽  
Lily R. Qiu ◽  
...  
Keyword(s):  
Brain Development ◽  
Brain Mri ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Adult Brain ◽  
Mutant Mice ◽  
Network Activity ◽  
Proteomic Profiling ◽  
Filamentous Actin

AbstractE3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

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 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 Glioma-Derived TSP2 Promotes Excitatory Synapse Formation and Results in Hyperexcitability in the Peritumoral Cortex of Glioma

2020 ◽  
Author(s):  
Yao-Hui Wang ◽  
Tian-Lan Huang ◽  
Xin Chen ◽  
Si-Xun Yu ◽  
Wei Li ◽  
...  
Keyword(s):  
Synapse Formation ◽  
Excitatory Synapse ◽  
Low Grade ◽  
Excitatory Synapses ◽  
Wild Type ◽  
Epileptiform Discharges ◽  
Stereotactic Implantation ◽  
Tissue Specimens ◽  
Insight Into

Abstract Seizures are common in patients with glioma, especially low-grade glioma (LGG). However, the epileptogenic mechanisms are poorly understood. Recent evidence has indicated that abnormal excitatory synaptogenesis plays an important role in epileptogenesis. The thrombospondin (TSP) family is a key regulator of synaptogenesis. Thus, this study aimed to elucidate the role of TSP2 in epileptogenesis in glioma-related epilepsy. The expression of TSP2 was increased in tumor tissue specimens from LGG patients, and this increase may have contributed to an increase in the density of spines and excitatory synapses in the peritumoral area. A glioma cell-implanted rat model was established by stereotactic implantation of wild-type TSP2-expressing, TSP2-overexpressing or TSP2-knockout C6 cells into the neocortex. Similarly, an increase in the density of excitatory synapses was also observed in the peritumoral area of the implanted tumor. In addition, epileptiform discharges occurred in the peritumoral cortex and were positively correlated with the TSP2 level in glioma tissues. Moreover, α2δ1/Rac1 signaling was enhanced in the peritumoral region, and treatment with the α2δ1 antagonist gabapentin inhibited epileptiform discharges in the peritumoral cortex. In conclusion, glioma-derived TSP2 promotes excitatory synapse formation, probably via the α2δ1/Rac1 signaling pathway, resulting in hyperexcitability in the peritumoral cortical networks, which may provide new insight into the epileptogenic mechanisms underlying glioma-related epilepsy.

scholarly journals Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

2020 ◽  
Author(s):  
Megha Amar ◽  
Akula Bala Pramod ◽  
Nam-Kyung Yu ◽  
Victor Munive Herrera ◽  
Lily R. Qiu ◽  
...  
Keyword(s):  
Brain Development ◽  
Brain Mri ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Mutant Mice ◽  
Network Activity ◽  
Proteomic Profiling ◽  
Filamentous Actin ◽  
Early Postnatal Development

SummaryE3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Autism Spectrum Disorder (ASD) and Developmental Delay (DD). To investigate how Cul3 mutations impact brain development, we generated haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified neuronal cytoskeleton and Rho signaling as primary targets of Cul3 mutation during early brain development.

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