scholarly journals Gephyrin-Lacking PV Synapses on Neocortical Pyramidal Neurons

2021 ◽  
Vol 22 (18) ◽  
pp. 10032
Author(s):  
Dika A. Kuljis ◽  
Kristina D. Micheva ◽  
Ajit Ray ◽  
Waja Wegner ◽  
Ryan Bowman ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Cell Activity ◽  
Inhibitory Synapses ◽  
Synaptic Density ◽  
Synaptic Localization ◽  
Fluorescence And Electron Microscopy ◽  
Acid Type ◽  
Specific Localization ◽  
Presynaptic Boutons ◽  
Post Synaptic Density

Gephyrin has long been thought of as a master regulator for inhibitory synapses, acting as a scaffold to organize γ-aminobutyric acid type A receptors (GABAARs) at the post-synaptic density. Accordingly, gephyrin immunostaining has been used as an indicator of inhibitory synapses; despite this, the pan-synaptic localization of gephyrin to specific classes of inhibitory synapses has not been demonstrated. Genetically encoded fibronectin intrabodies generated with mRNA display (FingRs) against gephyrin (Gephyrin.FingR) reliably label endogenous gephyrin, and can be tagged with fluorophores for comprehensive synaptic quantitation and monitoring. Here we investigated input- and target-specific localization of gephyrin at a defined class of inhibitory synapse, using Gephyrin.FingR proteins tagged with EGFP in brain tissue from transgenic mice. Parvalbumin-expressing (PV) neuron presynaptic boutons labeled using Cre- dependent synaptophysin-tdTomato were aligned with postsynaptic Gephyrin.FingR puncta. We discovered that more than one-third of PV boutons adjacent to neocortical pyramidal (Pyr) cell somas lack postsynaptic gephyrin labeling. This finding was confirmed using correlative fluorescence and electron microscopy. Our findings suggest some inhibitory synapses may lack gephyrin. Gephyrin-lacking synapses may play an important role in dynamically regulating cell activity under different physiological conditions.

Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

2019 ◽  
Vol 19 (5) ◽  
pp. 342-348 ◽  
Author(s):  
Zhi-You Cai ◽  
Chuan-Ling Wang ◽  
Tao-Tao Lu ◽  
Wen-Ming Yang
Keyword(s):  
Transgenic Mice ◽  
Western Blotting ◽  
Amyloid Β ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Synaptic Density ◽  
Ampk Signaling ◽  
The Brain ◽  
Post Synaptic Density

Background:Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.Methods:The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.Results:BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.Conclusion:BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

scholarly journals Myosin IIB Activity and Phosphorylation Status Determines Dendritic Spine and Post-Synaptic Density Morphology

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e24149 ◽  
Author(s):  
Jennifer L. Hodges ◽  
Karen Newell-Litwa ◽  
Hannelore Asmussen ◽  
Miguel Vicente-Manzanares ◽  
Alan Rick Horwitz
Keyword(s):  
Dendritic Spine ◽  
Synaptic Density ◽  
Post Synaptic Density

Glycoproteins of the post-synaptic density: biochemical and immunochemical characterization of PSD-GP180

1992 ◽  
Vol 20 (2) ◽  
pp. 379-382 ◽  
Author(s):  
J. W. Gurd ◽  
I. R. Brown ◽  
N. Bissoon ◽  
S. Cudmore ◽  
B. Ni ◽  
...  
Keyword(s):  
Synaptic Density ◽  
Immunochemical Characterization ◽  
Post Synaptic Density

scholarly journals Visual Deprivation Decreases Somatic GAD65 Puncta Number on Layer 2/3 Pyramidal Neurons in Mouse Visual Cortex

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Alicja Kreczko ◽  
Anubhuthi Goel ◽  
Lihua Song ◽  
Hey-Kyoung Lee
Keyword(s):  
Visual Cortex ◽  
Visual Experience ◽  
Pyramidal Neurons ◽  
Immunohistochemical Method ◽  
Inhibitory Synapses ◽  
Acid Decarboxylase ◽  
3D Analysis ◽  
Individual Layer ◽  
Inhibitory Circuitry ◽  
Layer 2

Proper functioning of the visual system depends on maturation of both excitatory and inhibitory synapses within the visual cortex. Considering that perisomatic inhibition is one of the key factors that control the critical period in visual cortex, it is pertinent to understand its regulation by visual experience. To do this, we developed an immunohistochemical method that allows three-dimensional (3D) analysis of the glutamic acid decarboxylase (GAD) 65-positive inhibitory terminals in the visual cortex. Using this method on transgenic mice expressing yellow fluorescence protein (YFP) in a subset of neurons, we found that the number of somatic GAD65-puncta on individual layer 2/3 pyramidal neurons is reduced when mice are dark-reared from birth and reverted to normal levels by re-exposure to light. There was no change in GAD65-puncta volume or intensity. These results support the reorganization of inhibitory circuitry within layer 2/3 of visual cortex in response to changes in visual experience.

scholarly journals Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions

Science ◽  
2019 ◽  
Vol 366 (6462) ◽  
pp. 246-250 ◽  
Author(s):  
Wenyan Han ◽  
Jun Li ◽  
Kenneth A. Pelkey ◽  
Saurabh Pandey ◽  
Xiumin Chen ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Clinical Importance ◽  
Aminobutyric Acid ◽  
Inhibitory Synapses ◽  
Channel Pore ◽  
Auxiliary Subunit ◽  
Deactivation Kinetics ◽  
Acid Type ◽  
Genetic Deletion ◽  
The Brain

The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore–forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABAARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.

scholarly journals The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ewoud R. E. Schmidt ◽  
Justine V. Kupferman ◽  
Michelle Stackmann ◽  
Franck Polleux
Keyword(s):  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Specific Gene ◽  
Dependent Manner ◽  
Synaptic Development ◽  
Synaptic Density ◽  
Synonymous Mutations ◽  
Arginine Residues ◽  
Human Specific

AbstractHuman-specific gene duplications (HSGDs) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGDs generated proteins that, in neurons, are intrinsically unstable and, upon hetero-dimerization with SRGAP2A, reduce SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique compared to SRGAP2B in its ability to induce long-lasting changes in synaptic density throughout adulthood. These mutations led to the ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.

Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

2012 ◽  
Vol 124 (3) ◽  
pp. 383-394 ◽  
Author(s):  
Naoya Aoki ◽  
Shinji Higashi ◽  
Ito Kawakami ◽  
Zen Kobayashi ◽  
Masato Hosokawa ◽  
...  
Keyword(s):  
Synaptic Density ◽  
Fused In Sarcoma ◽  
The Brain ◽  
Post Synaptic Density ◽  
Fus Protein
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