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 Presynaptic α2δ subunits are key organizers of glutamatergic synapses

2021 ◽  
Vol 118 (14) ◽  
pp. e1920827118
Author(s):  
Clemens L. Schöpf ◽  
Cornelia Ablinger ◽  
Stefanie M. Geisler ◽  
Ruslan I. Stanika ◽  
Marta Campiglio ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Metal Ion ◽  
Postsynaptic Density ◽  
Synaptic Proteins ◽  
Current View ◽  
Glutamatergic Synapses ◽  
Channel Trafficking ◽  
Presynaptic Differentiation ◽  
Presynaptic Calcium

In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels 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-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is 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. Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially 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. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, 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 transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.

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 Diversity of Mitochondrial Pathology in a Mouse Model of Axonal Degeneration in Synucleinopathies

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Akio Sekigawa ◽  
Yoshiki Takamatsu ◽  
Kazunari Sekiyama ◽  
Takato Takenouchi ◽  
Shuei Sugama ◽  
...  
Keyword(s):  
Axonal Degeneration ◽  
Lewy Bodies ◽  
Current View ◽  
Leucine Rich Repeat ◽  
Loss Of Function ◽  
Mitochondrial Quality Control ◽  
Axonal Pathology ◽  
Mitochondrial Pathology ◽  
Axonal Swellings

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis ofα-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD,α-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained inDrosophilaand cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressingα-synuclein or DLB-linked P123Hβ-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated inα-synuclein/LRRK2-immunopositive axonal swellings in mice expressingα-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123Hβ-synuclein, suggesting thatα- andβ-synuclein might play differential roles in the mitochondrial pathology ofα-synucleinopathies.

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 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.

The photoreceptor cytoskeleton visualized

1992 ◽  
Vol 50 (1) ◽  
pp. 480-481
Author(s):  
Beth Burnside
Keyword(s):  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Polarization ◽  
Synaptic Proteins ◽  
Cell Functions ◽  
Vertebrate Photoreceptor ◽  
Numerous Cell ◽  
Turn Over

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

mTORC and PKCε in Regulation of Alcohol Use Disorder

2020 ◽  
Vol 20 (17) ◽  
pp. 1696-1708 ◽  
Author(s):  
Athirah Hanim ◽  
Isa Naina Mohamed ◽  
Rashidi M. Pakri Mohamed ◽  
Srijit Das ◽  
Norefrina Shafinaz Md Nor ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Potential Role ◽  
Synaptic Proteins ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

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