scholarly journals Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

2017 ◽  
Vol 114 (4) ◽  
pp. E610-E618 ◽  
Author(s):  
Sonal Thakar ◽  
Liqing Wang ◽  
Ting Yu ◽  
Mao Ye ◽  
Keisuke Onishi ◽  
...  
Keyword(s):  
Synapse Formation ◽  
Conditional Knockout ◽  
Synaptic Proteins ◽  
Inhibitory Synapses ◽  
Spatial Learning And Memory ◽  
Spine Density ◽  
Glutamatergic Synapse ◽  
Glutamatergic Synapses ◽  
Core Components

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

scholarly journals The Impact of Oxytocin on Neurite Outgrowth and Synaptic Proteins in Magel2-Deficient Mice

2020 ◽  
Author(s):  
Alexandra Reichova ◽  
Fabienne Schaller ◽  
Stanislava Bukatova ◽  
Zuzana Bacova ◽  
Françoise Muscatelli ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Primary Cultures ◽  
Synaptic Proteins ◽  
Neuronal Maturation ◽  
Glutamatergic Synapses ◽  
Associated Proteins ◽  
The Impact ◽  
Deficient Mice

AbstractOxytocin contributes to the regulation of cytoskeletal and synaptic proteins and could therefore affect the mechanisms of neurodevelopmental disorders, including autism. Both the Prader-Willi syndrome and Schaaf-Yang syndrome exhibit autistic symptoms involving the MAGEL2 gene. Magel2-deficient mice show a deficit in social behavior that is rescued following postnatal administration of oxytocin. Here, in Magel2-deficient mice, we showed that the neurite outgrowth of primary cultures of immature hippocampal neurons is reduced. Treatment with oxytocin, but not retinoic acid, reversed this abnormality. In the hippocampus of Magel2-deficient pups, we further demonstrated that several transcripts of neurite outgrowth-associated proteins, synaptic vesicle proteins, and cell-adhesion molecules are decreased. In the juvenile stage, when neurons are mature, normalization or even overexpression of most of these markers was observed, suggesting a delay in the neuronal maturation of Magel2-deficient pups. Moreover, we found reduced transcripts of the excitatory postsynaptic marker, Psd95 in the hippocampus and we observed a decrease of PSD95/VGLUT2 colocalization in the hippocampal CA1 and CA3 regions in Magel2-deficient mice, indicating a defect in glutamatergic synapses. Postnatal administration of oxytocin upregulated postsynaptic transcripts in pups; however, it did not restore the level of markers of glutamatergic synapses in Magel2-deficient mice. Overall, Magel2 deficiency leads to abnormal neurite outgrowth and reduced glutamatergic synapses during development, suggesting abnormal neuronal maturation. Oxytocin stimulates the expression of numerous genes involved in neurite outgrowth and synapse formation in early development stages. Postnatal oxytocin administration has a strong effect in development that should be considered for certain neuropsychiatric conditions in infancy.

scholarly journals Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance

2019 ◽  
Author(s):  
Kelly A Jones ◽  
Michiko Sumiya ◽  
Kevin M Woolfrey ◽  
Deepak P Srivastava ◽  
Peter Penzes
Keyword(s):  
Ampa Receptors ◽  
Cortical Neurons ◽  
Glutamate Transporter ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Anterior Cingulate ◽  
Synaptic Proteins ◽  
Inhibitory Synapses ◽  
Nucleotide Exchange

EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras) and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of EPAC2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered of expression of vesicular glutamate transporter 1 (VGluT1) and vesicular GABA transporter (VGAT), indicating a potential imbalance in excitatory/inhibitory inputs onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that EPAC2 is required for the correct composition of synapses and that loss of this protein could result in an imbalance of excitatory and inhibitory synapses.

scholarly journals Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption

2021 ◽  
Vol 14 ◽  
Author(s):  
Takashi Hayashi
Keyword(s):  
Receptor Binding ◽  
Protein Modification ◽  
Recent Progress ◽  
Synaptic Proteins ◽  
Regulatory Mechanisms ◽  
Evolutionary Development ◽  
Glutamatergic Synapse ◽  
Glutamatergic Synapses ◽  
Excitatory Neurotransmitter ◽  
Vertebrate Brain

Glutamate is the major excitatory neurotransmitter in the vertebrate brain and various modifications have been established in the glutamatergic synapses. Generally, many neuronal receptors and ion channels are regulated by S-palmitoylation, a reversible post-translational protein modification. Genome sequence databases show the evolutionary acquisition and conservation concerning vertebrate-specific palmitoylation of synaptic proteins including glutamate receptors. Moreover, palmitoylation of some glutamate receptor-binding proteins is subsequently acquired only in some mammalian lineages. Recent progress in genome studies has revealed that some palmitoylation-catalyzing enzymes are the causative genes of neuropsychiatric disorders. In this review, I will summarize the evolutionary development of palmitoylation-dependent regulation of glutamatergic synapses and their dysfunctions which are caused by the disruption of palmitoylation mechanism.

scholarly journals Correct CYFIP1 dosage is essential for synaptic inhibition and the excitatory/inhibitory balance.

2018 ◽  
Author(s):  
Elizabeth C Davenport ◽  
Blanka Szulc ◽  
James Drew ◽  
James Taylor ◽  
Toby Morgan ◽  
...  
Keyword(s):  
Opposite Effect ◽  
Copy Number Variations ◽  
Conditional Knockout ◽  
Inhibitory Synapses ◽  
Synaptic Inhibition ◽  
Postsynaptic Currents ◽  
Synaptic Structure ◽  
And Function

Altered excitatory/inhibitory balance is implicated in neuropsychiatric disorders but the genetic aetiology of this is still poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia and intellectual disability but the role of CYFIP1 in regulating synaptic inhibition or excitatory/inhibitory balance remains unclear. We show, CYFIP1, and its paralogue CYFIP2, are enriched at inhibitory postsynaptic sites. While upregulation of CYFIP1 or CYFIP2 increased excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it had the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increased expression of postsynaptic GABA A receptor β2/3-subunits and neuroligin 3 and enhanced synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered excitatory/inhibitory balance and circuit dysfunction in CYFIP1-associated neurodevelopmental disorders.

scholarly journals Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights fromIn VivoRecordings in Neuroligin-1, Neuroligin-2, and Collybistin Knockouts

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Peter Jedlicka ◽  
Julia Muellerleile ◽  
Stephan W. Schwarzacher
Keyword(s):  
Synaptic Plasticity ◽  
Dentate Gyrus ◽  
Granule Cell ◽  
Molecular Mechanisms ◽  
Granule Cells ◽  
Functional Characterization ◽  
Inhibitory Synapses ◽  
Spatial Learning And Memory ◽  
Dentate Granule Cell

The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1) and inhibitory synapses (neuroligin-2 and collybistin).In vivorecordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.

scholarly journals Arhgap22 Disruption Leads to RAC1 Hyperactivity Affecting Hippocampal Glutamatergic Synapses and Cognition in Mice

2021 ◽  
Author(s):  
Anna Longatti ◽  
Luisa Ponzoni ◽  
Edoardo Moretto ◽  
Giorgia Giansante ◽  
Norma Lattuada ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Synapse Formation ◽  
Actin Dynamics ◽  
Spine Density ◽  
Glutamatergic Synapses ◽  
Synaptic Structure ◽  
Knockout Animal ◽  
Rac1 Activity ◽  
And Function

AbstractRho GTPases are a class of G-proteins involved in several aspects of cellular biology, including the regulation of actin cytoskeleton. The most studied members of this family are RHOA and RAC1 that act in concert to regulate actin dynamics. Recently, Rho GTPases gained much attention as synaptic regulators in the mammalian central nervous system (CNS). In this context, ARHGAP22 protein has been previously shown to specifically inhibit RAC1 activity thus standing as critical cytoskeleton regulator in cancer cell models; however, whether this function is maintained in neurons in the CNS is unknown. Here, we generated a knockout animal model for arhgap22 and provided evidence of its role in the hippocampus. Specifically, we found that ARHGAP22 absence leads to RAC1 hyperactivity and to an increase in dendritic spine density with defects in synaptic structure, molecular composition, and plasticity. Furthermore, arhgap22 silencing causes impairment in cognition and a reduction in anxiety-like behavior in mice. We also found that inhibiting RAC1 restored synaptic plasticity in ARHGAP22 KO mice. All together, these results shed light on the specific role of ARHGAP22 in hippocampal excitatory synapse formation and function as well as in learning and memory behaviors.

scholarly journals Presynaptic α2δ subunits are key organizers of glutamatergic synapses

2019 ◽  
Author(s):  
Clemens L. Schöpf ◽  
Stefanie Geisler ◽  
Ruslan I. Stanika ◽  
Marta Campiglio ◽  
Walter A. Kaufmann ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Synapse Formation ◽  
Postsynaptic Density ◽  
Synaptic Proteins ◽  
Current View ◽  
Loss Of Function ◽  
Glutamatergic Synapses ◽  
Channel Trafficking ◽  
Presynaptic Differentiation

In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels (VGCCs) have been linked to synaptic functions and neurological disease. Here we show that α2δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α2δ subunit triple loss-of-function model, we demonstrate a failure in presynaptic differentiation associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms as synaptic organizers is highly redundant, as each individual α2δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Mutating the MIDAS site in α2δ-2 dissociates rescuing presynaptic synapsin expression from calcium channel trafficking, suggesting that the regulatory role of α2δ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. Firstly, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Secondly, the dependence of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α2δ subunits act as trans-synaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.

scholarly journals Interferon-ɣ Exposure of Human iPSC-derived Neurons Alters Major Histocompatibility Complex I and Synapsin I Protein Expression

2021 ◽  
Author(s):  
Adam Pavelinek ◽  
Rugile Matuleviciute ◽  
Laura Sichlinger ◽  
Lucia Dutan Polit ◽  
Nikos Armeniakos ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Synaptic Proteins ◽  
Synapsin I ◽  
Mrna Levels ◽  
Maternal Immune Activation ◽  
Increased Risk

Human epidemiological data links maternal immune activation during gestation with increased risk for neurodevelopmental disorders including schizophrenia. Animal models of maternal immune activation (MIA) provide causal evidence for this association and strongly suggest that inflammatory cytokines act is a critical link between maternal infection and aberrant offspring brain and behavior development. This includes evidence for reduced synapse formation, consistent with post-mortem and in vivo evidence of reduced synaptic density in schizophrenia. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. Using a human cellular model, we recently demonstrated that acute exposure to interferon-ɣ (IFNɣ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNɣ affects synapse formation in an induced neuron model that generates forebrain glutamatergic neurons. Using immunocytochemistry and quantitative PCR, we demonstrate that acute IFNɣ exposure results in significantly increased MHCI expression at the mRNA and protein level. Furthermore, acute IFNɣ exposure decreases synapsin I protein in neurons but does not affect synaptic gene mRNA levels. Interestingly, complement component 4A (C4A) mRNA is also significantly increased following acute IFNɣ exposure. This study builds on our previous work by showing that IFNɣ-mediated disruption of relevant synaptic proteins can occur at early stages of synapse formation, potentially contributing to neurodevelopmental disorder phenotypes such as schizophrenia.

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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