scholarly journals Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model

2020 ◽  
Author(s):  
Shan-Xue Jin ◽  
Haruki Higashimori ◽  
Christina Schin ◽  
Alessandra Tamashiro ◽  
Yuqin Men ◽  
...  
Keyword(s):  
Glutamate Uptake ◽  
Fragile X ◽  
Cell Types ◽  
Skill Learning ◽  
Spine Density ◽  
Novelty Preference ◽  
Synaptic Signaling ◽  
Selective Loss ◽  
State Duration ◽  
Cortical Hyperexcitability

AbstractFragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.

Generation of Slow Network Oscillations in the Developing Rat Hippocampus After Blockade of Glutamate Uptake

2007 ◽  
Vol 98 (4) ◽  
pp. 2324-2336 ◽  
Author(s):  
Adriano Augusto Cattani ◽  
Valérie Delphine Bonfardin ◽  
Alfonso Represa ◽  
Yehezkel Ben-Ari ◽  
Laurent Aniksztejn
Keyword(s):  
Nmda Receptors ◽  
Glutamate Uptake ◽  
Pyramidal Cells ◽  
Cell Types ◽  
Proper Function ◽  
Network Oscillations ◽  
Bath Application ◽  
Hippocampal Network

Cell-surface glutamate transporters are essential for the proper function of early cortical networks because their dysfunction induces seizures in the newborn rat in vivo. We have now analyzed the consequences of their inhibition by dl-TBOA on the activity of the developing CA1 rat hippocampal network in vitro. dl-TBOA generated a pattern of recurrent depolarization with an onset and decay of several seconds' duration in interneurons and pyramidal cells. These slow network oscillations (SNOs) were mostly mediated by γ-aminobutyric acid (GABA) in pyramidal cells and by GABA and N-methyl-d-aspartate (NMDA) receptors in interneurons. However, in both cell types SNOs were blocked by NMDA receptor antagonists, suggesting that their generation requires a glutamatergic drive. Moreover, in interneurons, SNOs were still generated after the blockade of NMDA-mediated synaptic currents with MK-801, suggesting that SNOs are expressed by the activation of extrasynaptic NMDA receptors. Long-lasting bath application of glutamate or NMDA failed to induce SNOs, indicating that they are generated by periodic but not sustained activation of NMDA receptors. In addition, SNOs were observed in interneurons recorded in slices with or without the strata pyramidale and oriens, suggesting that the glutamatergic drive may originate from the radiatum and pyramidale strata. We propose that in the absence of an efficient transport of glutamate, the transmitter diffuses in the extracellular space to activate extrasynaptic NMDA receptors preferentially present on interneurons that in turn activate other interneurons and pyramidal cells. This periodic neuronal coactivation may contribute to the generation of seizures when glutamate transport dysfunction is present.

gp120-induced alterations of human astrocyte function: Na+/H+exchange, K+conductance, and glutamate flux

2000 ◽  
Vol 279 (3) ◽  
pp. C700-C708 ◽  
Author(s):  
Holly K. Patton ◽  
Zhen-Hong Zhou ◽  
James K. Bubien ◽  
Etty N. Benveniste ◽  
Dale J. Benos
Keyword(s):  
Glutamate Uptake ◽  
Cell Types ◽  
Neurological Complications ◽  
Ph Sensitive ◽  
Human Astrocyte ◽  
Physiological Processes ◽  
Human Astrocytes ◽  
Rat Astrocytes ◽  
Immunodeficiency Syndrome ◽  
Intracellular Alkalinization

Many human immunodeficiency virus (HIV)-infected patients suffer from impaired neurological function and dementia. This facet of the disease has been termed acquired immunodeficiency syndrome (AIDS)-associated dementia complex (ADC). Several cell types, including astrocytes and neurons, are not productively infected by virus but are involved in ADC pathophysiology. Previous studies of rat astrocytes showed that an HIV coat protein (gp120) accelerated astrocyte Na+/H+exchange and that the resultant intracellular alkalinization activated a pH-sensitive K+conductance. The present experiments were conducted to determine whether gp120 affected human astrocytes in the same fashion. It was found that primary human astrocytes express a pH-sensitive K+conductance that was activated on intracellular alkalinization. Also, gp120 treatment of whole cell clamped human astrocytes activated this conductance specifically. Furthermore, gp120 inhibited glutamate uptake by primary human astrocytes. These altered physiological processes could contribute to pathophysiological changes in HIV-infected brains. Because the gp120-induced cell physiological changes were partially inhibited by dimethylamiloride (an inhibitor of Na+/H+exchange), our findings suggest that modification of human astrocyte Na+/H+exchange activity may provide a means of addressing some of the neurological complications of HIV infection.

scholarly journals Altered Structural and Functional Synaptic Plasticity with Motor Skill Learning in a Mouse Model of Fragile X Syndrome

2013 ◽  
Vol 33 (50) ◽  
pp. 19715-19723 ◽  
Author(s):  
R. Padmashri ◽  
B. C. Reiner ◽  
A. Suresh ◽  
E. Spartz ◽  
A. Dunaevsky
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Motor Skill ◽  
Fragile X ◽  
Skill Learning ◽  
Motor Skill Learning

scholarly journals Sex and pubertal status influence dendritic spine density onto frontal corticostriatal projection neurons

2019 ◽  
Author(s):  
Kristen Delevich ◽  
Nana J. Okada ◽  
Ameet Rahane ◽  
Zicheng Zhang ◽  
Christopher D. Hall ◽  
...  
Keyword(s):  
Adolescent Development ◽  
Dendritic Spine ◽  
Cell Types ◽  
Projection Neurons ◽  
Spine Density ◽  
Adult Males ◽  
Puberty Onset ◽  
Spatial Topography ◽  
Different Cell Types ◽  
Spine Pruning

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends late into adolescence. This protracted maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how different cell types in the frontal cortex mature or whether puberty plays a role. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project to the dorsomedial striatum (DMS). We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in males.

scholarly journals The coordinated localization of mRNA to centrosomes facilitates error-free mitosis

2020 ◽  
Author(s):  
Pearl V. Ryder ◽  
Junnan Fang ◽  
Dorothy A. Lerit
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Fragile X ◽  
Protein Localization ◽  
Cell Types ◽  
Rna Granules ◽  
Mental Retardation Protein ◽  
Pericentriolar Material ◽  
Cycle Dependent ◽  
Post Transcriptional Regulation

AbstractCentrosomes are microtubule-organizing centers required for error-free mitosis and embryonic development. The microtubule-nucleating activity of centrosomes is conferred by the pericentriolar material (PCM), a composite of numerous proteins subject to cell cycle-dependent oscillations in levels and organization. In diverse cell types, mRNAs localize to centrosomes and may contribute to changes in PCM abundance. Here, we investigate the regulation of mRNA localization to centrosomes in the rapidly cycling Drosophila melanogaster embryo. We find that RNA localization to centrosomes is regulated during the cell cycle and developmentally. We identify a novel role for the fragile-X mental retardation protein (FMRP), which localizes to pericentrosomal RNA granules, in the post-transcriptional regulation of centrosomal RNA. Further, the mis-targeting of a model centrosomal mRNA, centrocortin (cen), is sufficient to alter cognate protein localization to centrosomes and impair spindle morphogenesis and genome stability.

scholarly journals FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

2019 ◽  
Author(s):  
Sarah J. Van Driesche ◽  
Kirsty Sawicka ◽  
Chaolin Zhang ◽  
Sharon K.Y. Hung ◽  
Christopher Y. Park ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Fragile X ◽  
Neuronal Cell ◽  
Transcript Abundance ◽  
Cell Types ◽  
Loss Of Function ◽  
Ip3 Receptor ◽  
Mrna Targets ◽  
Ranked List

SummaryLoss of function of the Fragile X Mental Retardation Protein (FMRP) in human Fragile X Syndrome (FXS) and in model organisms results in phenotypes of abnormal neuronal structure and dynamics, synaptic function and connectivity which may contribute to a state of neuronal, circuit and organism hyperexcitability. Previousin vivoidentification of FMRP association with specific mRNA targets in mouse brain revealed that FMRP regulates the translation of a large fraction of the synaptic proteome in both pre- and post-synaptic compartments as well as many transcription factors and chromatin modifying proteins. However, it was not previously possible to determine the ratio of FMRP binding to transcript abundance due to the complexity of different neuronal cell types in whole brain. Moreover, it has been difficult to link the translational regulation of specific targets to model phenotypes or human symptoms. For example, loss-of-function of FMRP in the Purkinje cells of the cerebellum results in three cell autonomous phenotypes related to learning and memory, including enhanced mGluR-LTD at parallel fiber synapses, altered dendritic spines and behavioral deficits in a eyeblink-conditioning learning paradigm shared by human FXS patients. The molecular basis for these and related human Fragile X phenotypes is unknown. To address these critical issues we have developed a new mouse model (theFmr1cTAG mouse) in which endogenous FMRP can be conditionally tagged for RNA:protein crosslinking and immunoprecipitation (CLIP) identification of the RNAs with which it interactsin vivo. We used theFmr1cTAG mouse to quantitatively evaluate FMRP-mRNA association in Purkinje and cerebellar granule neurons which together comprise the parallel-fiber synapse. We calculated a stoichiometrically ranked list of FMRP RNA binding events by normalizing to ribosome-associated transcript abundance determined by TRAP-seq, and now definitively find that FMRP associates with specific sets of mRNAs which differ between the two cell types. In Purkinje cells, many components of the mGluR signaling pathway are FMRP targets including the top-ranked Purkinje cell mRNAItpr1, encoding the IP3 receptor, the function of which is critical to proper mGluR-dependent synaptic plasticity. In sum, this novel approach provides the first ranked list of FMRP target mRNAs and further reveals that FMRP regulates a specific set of long neural genes related to relevant cell autonomous phenotypes.HighlightsWe have created a mouse model in which endogenous FMRP can be conditionally tagged.Using tag-specific CLIP we describe ranked and specific sets ofin vivoFMRP mRNA targets in two types of neurons.This ranking was used to reveal that FMRP regulates mRNAs with long coding sequences.FMRP mRNA targets in Purkinje cells, including the top-ranked IP3 receptor, are related to cell-autonomous Fragile X phenotypes.We have updated our previous list of whole mouse brain FMRP mRNA targets with more replicates, deeper sequencing and improved analysisThe use of tagged FMRP in less abundant cell populations allowed identification of novel mRNA targets missed in a whole brain analysis

scholarly journals Synaptic processes and immune-related pathways implicated in Tourette Syndrome

2020 ◽  
Author(s):  
Fotis Tsetsos ◽  
Dongmei Yu ◽  
Jae Hoon Sul ◽  
Alden Y. Huang ◽  
Cornelia Illmann ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Ion Channel ◽  
Tourette Syndrome ◽  
Cell Types ◽  
Synaptic Signaling ◽  
Gene Set ◽  
Individual Level ◽  
Genome Wide ◽  
Additional Support

AbstractTourette Syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with Tourette Syndrome (TS) and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating Ligand-gated Ion Channel Signaling, Lymphocytic, and Cell Adhesion and Trans-synaptic Signaling processes. MAGMA analysis further supported the involvement of the Cell Adhesion and Trans-synaptic Signaling gene set. The Lympho-cytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of Ligand-gated Ion Channel Signaling reinforce the role of GABA in TS, while the association of Cell Adhesion and Trans-synaptic Signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders.

scholarly journals Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Antonella Ferrante ◽  
Zaira Boussadia ◽  
Antonella Borreca ◽  
Cinzia Mallozzi ◽  
Giorgia Pedini ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Neuronal Damage ◽  
Fragile X ◽  
Hippocampal Slices ◽  
Excitatory Postsynaptic Potential ◽  
Spine Density ◽  
Behavioral Alterations ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptors ◽  
Hippocampal Alterations

AbstractIn fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A2A receptors (A2ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A2ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A2AR antagonist ZM241385 and strongly potentiated by the A2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A2AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A2AR-related downstream targets.

scholarly journals Extensive GJD2 Expression in the Song Motor Pathway Reveals the Extent of Electrical Synapses in the Songbird Brain

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1099
Author(s):  
Pepe Alcami ◽  
Santhosh Totagera ◽  
Nina Sohnius-Wilhelmi ◽  
Stefan Leitner ◽  
Benedikt Grothe ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Types ◽  
Brain Regions ◽  
Skill Learning ◽  
Electrical Synapse ◽  
Suitable Model ◽  
Sequencing Data ◽  
Electrical Synapses ◽  
Connexin 36 ◽  
Chemical Synapses

Birdsong is a precisely timed animal behavior. The connectivity of song premotor neural networks has been proposed to underlie the temporal patterns of neuronal activity that control vo-cal muscle movements during singing. Although the connectivity of premotor nuclei via chemical synapses has been characterized, electrical synapses and their molecular identity remain unex-plored. We show with in situ hybridizations that GJD2 mRNA, coding for the major channel-form-ing electrical synapse protein in mammals, connexin 36, is expressed in the two nuclei that control song production, HVC and RA from canaries and zebra finches. In canaries’ HVC, GJD2 mRNA is extensively expressed in GABAergic and only a fraction of glutamatergic cells. By contrast, in RA, GJD2 mRNA expression is widespread in glutamatergic and GABAergic neurons. Remarkably, GJD2 expression is similar in song nuclei and their respective embedding brain regions, revealing the widespread expression of GJD2 in the avian brain. Inspection of a single-cell sequencing data-base from zebra and Bengalese finches generalizes the distributions of electrical synapses across cell types and song nuclei that we found in HVC and RA from canaries, reveals a differential GJD2 mRNA expression in HVC glutamatergic subtypes and its transient increase along the neurogenic lineage. We propose that songbirds are a suitable model to investigate the contribution of electrical synapses to motor skill learning and production.

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