scholarly journals Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

2021 ◽  
Vol 9 ◽  
Author(s):  
Bryce W. Duncan ◽  
Kelsey E. Murphy ◽  
Patricia F. Maness
Keyword(s):  
Adhesion Molecules ◽  
Molecular Mechanisms ◽  
Inhibitory Synapses ◽  
Mammalian Brain ◽  
Synaptic Membranes ◽  
Critical Periods ◽  
Perineuronal Net ◽  
Synaptic Regulation ◽  
Ligand Interactions ◽  
Excitatory And Inhibitory Synapses

Mammalian brain circuits are wired by dynamic formation and remodeling during development to produce a balance of excitatory and inhibitory synapses. Synaptic regulation is mediated by a complex network of proteins including immunoglobulin (Ig)- class cell adhesion molecules (CAMs), structural and signal-transducing components at the pre- and post-synaptic membranes, and the extracellular protein matrix. This review explores the current understanding of developmental synapse regulation mediated by L1 and NCAM family CAMs. Excitatory and inhibitory synapses undergo formation and remodeling through neuronal CAMs and receptor-ligand interactions. These responses result in pruning inactive dendritic spines and perisomatic contacts, or synaptic strengthening during critical periods of plasticity. Ankyrins engage neural adhesion molecules of the L1 family (L1-CAMs) to promote synaptic stability. Chondroitin sulfates, hyaluronic acid, tenascin-R, and linker proteins comprising the perineuronal net interact with L1-CAMs and NCAM, stabilizing synaptic contacts and limiting plasticity as critical periods close. Understanding neuronal adhesion signaling and synaptic targeting provides insight into normal development as well as synaptic connectivity disorders including autism, schizophrenia, and intellectual disability.

scholarly journals Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Christine Gottschling ◽  
David Wegrzyn ◽  
Bernd Denecke ◽  
Andreas Faissner
Keyword(s):  
Extracellular Matrix ◽  
Neuronal Network ◽  
Knockout Mouse ◽  
Activity Level ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Mammalian Brain ◽  
Tenascin C ◽  
Neuronal Network Activity ◽  
Excitatory And Inhibitory Synapses

Abstract The synaptic transmission in the mammalian brain is not limited to the interplay between the pre- and the postsynapse of neurons, but involves also astrocytes as well as extracellular matrix (ECM) molecules. Glycoproteins, proteoglycans and hyaluronic acid of the ECM pervade the pericellular environment and condense to special superstructures termed perineuronal nets (PNN) that surround a subpopulation of CNS neurons. The present study focuses on the analysis of PNNs in a quadruple knockout mouse deficient for the ECM molecules tenascin-C (TnC), tenascin-R (TnR), neurocan and brevican. Here, we analysed the proportion of excitatory and inhibitory synapses and performed electrophysiological recordings of the spontaneous neuronal network activity of hippocampal neurons in vitro. While we found an increase in the number of excitatory synaptic molecules in the quadruple knockout cultures, the number of inhibitory synaptic molecules was significantly reduced. This observation was complemented with an enhancement of the neuronal network activity level. The in vivo analysis of PNNs in the hippocampus of the quadruple knockout mouse revealed a reduction of PNN size and complexity in the CA2 region. In addition, a microarray analysis of the postnatal day (P) 21 hippocampus was performed unravelling an altered gene expression in the quadruple knockout hippocampus.

Trafficking and Activity of Glutamate and GABA Receptors: Regulation by Cell Adhesion Molecules

2020 ◽  
Vol 26 (5-6) ◽  
pp. 415-437
Author(s):  
Ryan Keable ◽  
Iryna Leshchyns’ka ◽  
Vladimir Sytnyk
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Gaba Receptors ◽  
Cell Adhesion Molecules ◽  
Gene Mutations ◽  
Synaptic Strength ◽  
Inhibitory Synapses ◽  
Single Receptor ◽  
Synaptic Pathology ◽  
Excitatory And Inhibitory Synapses

The efficient targeting of ionotropic receptors to postsynaptic sites is essential for the function of chemical excitatory and inhibitory synapses, constituting the majority of synapses in the brain. A growing body of evidence indicates that cell adhesion molecules (CAMs), which accumulate at synapses at the earliest stages of synaptogenesis, are critical for this process. A diverse variety of CAMs assemble into complexes with glutamate and GABA receptors and regulate the targeting of these receptors to the cell surface and synapses. Presynaptically localized CAMs provide an additional level of regulation, sending a trans-synaptic signal that can regulate synaptic strength at the level of receptor trafficking. Apart from controlling the numbers of receptors present at postsynaptic sites, CAMs can also influence synaptic strength by modulating the conductivity of single receptor channels. CAMs thus act to maintain basal synaptic transmission and are essential for many forms of activity dependent synaptic plasticity. These activities of CAMs may underlie the association between CAM gene mutations and synaptic pathology and represent fundamental mechanisms by which synaptic strength is dynamically tuned at both excitatory and inhibitory synapses.

scholarly journals An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity

2021 ◽  
Vol 22 (5) ◽  
pp. 2434
Author(s):  
Daniela Carulli ◽  
Joost Verhaagen
Keyword(s):  
Critical Period ◽  
Brain Plasticity ◽  
Time Windows ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Postnatal Life ◽  
Perineuronal Nets ◽  
Critical Periods ◽  
Perineuronal Net ◽  
Memory Processes

During restricted time windows of postnatal life, called critical periods, neural circuits are highly plastic and are shaped by environmental stimuli. In several mammalian brain areas, from the cerebral cortex to the hippocampus and amygdala, the closure of the critical period is dependent on the formation of perineuronal nets. Perineuronal nets are a condensed form of an extracellular matrix, which surrounds the soma and proximal dendrites of subsets of neurons, enwrapping synaptic terminals. Experimentally disrupting perineuronal nets in adult animals induces the reactivation of critical period plasticity, pointing to a role of the perineuronal net as a molecular brake on plasticity as the critical period closes. Interestingly, in the adult brain, the expression of perineuronal nets is remarkably dynamic, changing its plasticity-associated conditions, including memory processes. In this review, we aimed to address how perineuronal nets contribute to the maturation of brain circuits and the regulation of adult brain plasticity and memory processes in physiological and pathological conditions.

scholarly journals BMP signaling alters aquaporin-4 expression in the mouse cerebral cortex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazuya Morita ◽  
Naoyuki Matsumoto ◽  
Kengo Saito ◽  
Toshihide Hamabe-Horiike ◽  
Keishi Mizuguchi ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Molecular Mechanisms ◽  
Water Movement ◽  
Water Channel ◽  
Bmp Signaling ◽  
Aquaporin 4 ◽  
Mammalian Brain ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
Mouse Cerebral Cortex

AbstractAquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.

Why is the perceptual octave stretched? An account based on mismatched time constants within the auditory brainstem

2021 ◽  
Author(s):  
Alain de Cheveigné
Keyword(s):  
Time Constant ◽  
Auditory Brainstem ◽  
The Other ◽  
Inhibitory Synapses ◽  
Coincidence Counting ◽  
Time Constants ◽  
Direct Pathway ◽  
Lower Tone ◽  
Excitatory And Inhibitory Synapses

This paper suggests an explanation for listener’s greater tolerance to positive than negative mistuning of the higher tone within an octave pair. It hypothesizes a neu- ral circuit tuned to cancel the lower tone, that also cancels the higher tone if that tone is in tune. Imperfect cancellation is the cue to mistuning of the octave. The circuit involves two pathways, one delayed with respect to the other, that feed a coincidence-counting neuron via excitatory and inhibitory synapses. A mismatch between the time constants of these two synapses results in an asymmetry in sen- sitivity to mismatch. Specifically, if the time constant of the delayed pathway is greater than that of the direct pathway, there is a greater tolerance to positive than to negative mistuning, which can lead to a perceptual“stretch” of the octave. The model is applicable to both harmonic and – with qualification – melodic oc- taves. The paper describes the model and reviews the evidence from auditory psychophysics and physiology in favor – or against – it.

scholarly journals Molecular Cloning, Characterization, and Chromosome Mapping of Reptilian Estrogen Receptors

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5710-5720 ◽  
Author(s):  
Yoshinao Katsu ◽  
Kazumi Matsubara ◽  
Satomi Kohno ◽  
Yoichi Matsuda ◽  
Michihisa Toriba ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Hormone Receptor ◽  
Molecular Mechanisms ◽  
Steroid Hormone ◽  
Chromosome 1 ◽  
Sex Steroid ◽  
Steroid Hormone Receptor ◽  
Sex Steroid Hormone ◽  
Ligand Interactions ◽  
Rat Snake

In many vertebrates, steroid hormones are essential for ovarian differentiation during a critical developmental stage as well as promoting the growth and differentiation of the adult female reproductive system. Although studies have been extensively conducted in mammals and a few fish, amphibians, and bird species, the molecular mechanisms of sex steroid hormone (estrogens) action have been poorly examined in reptiles. Here, we evaluate hormone receptor and ligand interactions in two species of snake, the Okinawa habu (Protobothrops flavoviridis, Viperidae) and the Japanese four-striped rat snake (Elaphe quadrivirgata, Colubridae) after the isolation of cDNAs encoding estrogen receptor α (ESR1) and estrogen receptor β (ESR2). Using a transient transfection assay with mammalian cells, the transcriptional activity of reptilian (Okinawa habu, Japanese four-striped rat snake, American alligator, and Florida red-belly freshwater turtle) ESR1 and ESR2 was examined. All ESR proteins displayed estrogen-dependent activation of transcription via an estrogen-response element-containing promoter; however, the responsiveness to various estrogens was different. Further, we determined the chromosomal locations of the snake steroid hormone receptor genes. ESR1 and ESR2 genes were localized to the short and long arms of chromosome 1, respectively, whereas androgen receptor was localized to a pair of microchromosomes in the two snake species examined. These data provide basic tools that allow future studies examining receptor-ligand interactions and steroid endocrinology in snakes and also expands our knowledge of sex steroid hormone receptor evolution.

scholarly journals Elucidating Binding Sites and Affinities of ERα Agonist and Antagonist to Human Alpha-Fetoprotein by in silico Modeling and Point Mutagenesis

2019 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Daria S. Ostroverkhova ◽  
Nikolai N. Kuzmich ◽  
Vladimir V. Kadochnikov ◽  
Alexander A. Terentiev ◽  
...  
Keyword(s):  
Binding Sites ◽  
In Silico ◽  
Disulfide Bonds ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Scoring Function ◽  
Alpha Fetoprotein ◽  
Ligand Interaction ◽  
Ligand Interactions

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (ΔGbind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

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