scholarly journals Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity

2021 ◽  
Author(s):  
Raphael Dos Reis ◽  
Etienne Kornobis ◽  
Alyssa Pereira ◽  
Frédéric Tores ◽  
Judit Carrasco ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Neurological Diseases ◽  
Neuropsychiatric Disorders ◽  
Inhibitory Synapses ◽  
Gaba A ◽  
Human Brain Development ◽  
Multiple Alternative ◽  
Splicing Defects ◽  
Complex Regulation ◽  
Cerebellar Purkinje Cells

Abstract Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and GABA-A receptors containing synapses. They exhibit different localization and postsynaptic clustering properties, and altering the expression level of one isoform is sufficient to affect the number, size, and density of inhibitory synapses in cerebellar Purkinje cells. Furthermore, we discovered that splicing defects reported in neuropsychiatric disorders are carried by multiple alternative GPHN transcripts, demonstrating the need for a thorough analysis of the GPHN transcriptome in patients. Overall, we show that alternative splicing of GPHN is an important genetic variation to consider in neurological diseases and a determinant of the diversity of postsynaptic inhibitory synapses.

scholarly journals Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders

2021 ◽  
Author(s):  
Manuela R. Kouakou ◽  
Darren Cameron ◽  
Eilis Hannon ◽  
Emma L. Dempster ◽  
Jonathan Mill ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Major Depressive Disorder ◽  
Genetic Variation ◽  
Frontal Cortex ◽  
Fetal Brain ◽  
Neuropsychiatric Disorders ◽  
Open Chromatin ◽  
Major Depressive ◽  
Genomic Regions ◽  
Neuropsychiatric Conditions

Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used ATAC-Seq to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN- nuclei from the prenatal human frontal cortex, and tested enrichment of SNP heritability for 5 neuropsychiatric disorders (autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder and schizophrenia within open chromatin regions mapped in bulk fetal frontal cortex, and for all 5 tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in open chromatin regions identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped open chromatin regions for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN- cells of the prenatal brain.

scholarly journals The Bacterial Enzyme RfxCas13d Is Less Neurotoxic Than PspCas13b and Could Be a Promising RNA Editing and Interference Tool in the Nervous System

2021 ◽  
Vol 11 (8) ◽  
pp. 1054
Author(s):  
Qin-Wei Wu ◽  
Josef P. Kapfhammer
Keyword(s):  
Nervous System ◽  
Purkinje Cells ◽  
Rna Editing ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Significant Inhibition ◽  
Great Promise ◽  
Bacterial Enzymes ◽  
Dendritic Development ◽  
Cerebellar Purkinje Cells

RNA therapies using RNA editing and interference are currently being developed for neurological diseases. The CRISPR-Cas13 system, based on bacterial enzymes, holds great promise for developing efficient tools for RNA therapies. However, neurotoxic activity has been reported for Cas13a, and recent studies have reported toxic effects of PspCas13b and RfxCas13d during zebrafish and Drosophila embryonic development. It is important to investigate the safety of these bacterial enzymes in the context of the nervous system and neuronal development. In this study, we used mouse cerebellar Purkinje cells as a complex neuron type to test for the potential neurotoxic actions of RfxCas13d and PspCas13b. We found that PspCas13b significantly impeded the dendritic development of cultured Purkinje cells, similar to the neurotoxic action of Cas13a. In contrast, RfxCas13d did not exhibit a significant inhibition of dendritic development. A similar trend was found for axonal outgrowth. These results suggest varying neurotoxic properties for different Cas13 ortholog enzymes. We call for more studies to investigate, and possibly mitigate, the neurotoxicity of Cas13 proteins in order to improve the safety of the CRISPR-Cas13 system for RNA therapies.

Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells

2014 ◽  
Vol 39 (8) ◽  
pp. 1268-1280 ◽  
Author(s):  
Aya Ito-Ishida ◽  
Wataru Kakegawa ◽  
Kazuhisa Kohda ◽  
Eriko Miura ◽  
Shigeo Okabe ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Inhibitory Synapses ◽  
Cerebellar Purkinje Cells ◽  
And Function

scholarly journals Microglial Cell Morphology and Phagocytic Activity Are Critically Regulated by the Neurosteroid Allopregnanolone: A Possible Role in Neuroprotection

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 698
Author(s):  
Valérie Jolivel ◽  
Susana Brun ◽  
Fabien Binamé ◽  
Jérémie Benyounes ◽  
Omar Taleb ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Phagocytic Activity ◽  
Microglial Cell ◽  
Neurological Diseases ◽  
Time Lapse ◽  
Microglial Cells ◽  
Primary Microglia ◽  
Gaba A ◽  
Neuroprotective Strategies ◽  
Underlying Mechanisms

Microglial cells are key players in neural pathogenesis and microglial function regulation appears to be pivotal in controlling neuroinflammatory/neurological diseases. Here, we investigated the effects and mechanism of action of neurosteroid allopregnanolone (ALLO) on murine microglial BV-2 cells and primary microglia in order to determine ALLO-induced immunomodulatory potential and to provide new insights for the development of both natural and safe neuroprotective strategies targeting microglia. Indeed, ALLO-treatment is increasingly suggested as beneficial in various models of neurological disorders but the underlying mechanisms have not been elucidated. Therefore, the microglial cells were cultured with various serum concentrations to mimic the blood-brain-barrier rupture and to induce their activation. Proliferation, viability, RT-qPCR, phagocytosis, and morphology analyzes, as well as migration with time-lapse imaging and quantitative morphodynamic methods, were combined to investigate ALLO actions on microglia. BV-2 cells express subunits of GABA-A receptor that mediates ALLO activity. ALLO (10µM) induced microglial cell process extension and decreased migratory capacity. Interestingly, ALLO modulated the phagocytic activity of BV-2 cells and primary microglia. Our results, which show a direct effect of ALLO on microglial morphology and phagocytic function, suggest that the natural neurosteroid-based approach may contribute to developing effective strategies against neurological disorders that are evoked by microglia-related abnormalities.

scholarly journals Chronic Cerebral Toxoplasmosis Changes Brain Glutamate and D-Serine Levels, Impairs Startle Reflex But Not Social Preference in Mice

2021 ◽  
Author(s):  
Mariana Acquarone ◽  
André Poleto ◽  
Ananda Perozzo ◽  
Patricia Gonçalves ◽  
Rogério Panizzutti ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Social Preference ◽  
Neurological Diseases ◽  
Chronic Phase ◽  
Tail Suspension Test ◽  
Neuropsychiatric Disorders ◽  
Cerebral Toxoplasmosis ◽  
Startle Amplitude ◽  
The Central Nervous System

Abstract Toxoplasma gondii is an opportunistic protozoan pathogen with a wide geographic distribution. The chronic phase of toxoplasmosis is often asymptomatic in humans and is characterized by tissue cysts throughout the central nervous system and muscle cells. T. gondii and other pathogens with tropism for the central nervous system are considered risk factors in the etiology of several neuropsychiatric disorders, such as schizophrenia and bipolar disorder, besides neurological diseases. Currently, it is known that cerebral toxoplasmosis increases dopamine levels in the brain and it is related to behavioral changes in animals and humans. Here we evaluate whether chronic T. gondii infection, using the cystogenic ME-49 strain, could induce behavioral alterations associated with neuropsychiatric disorders and glutamatergic neurotransmission dysfunction. We observed that the startle amplitude is reduced in the infected animals as well as glutamate and D-serine levels in prefrontal cortical and hippocampal tissue homogenates. Moreover, we did not detect alterations in social preference, spontaneous alternation, and tail suspension test despite severe motor impairment. Thus, we conclude that behavioral and cognitive aspects are maintained even though severe neural damage is observed by chronic infection of C57Bl/6 mice with the ME-49 strain.

scholarly journals Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Anna Rocchi ◽  
Silvio Sacchetti ◽  
Antonio De Fusco ◽  
Silvia Giovedi ◽  
Barbara Parisi ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Neurological Diseases ◽  
Synaptic Function ◽  
Inhibitory Synapses ◽  
Synapsin I ◽  
Loss Of Function ◽  
Reduced Density ◽  
Cytoplasmic Side

AbstractSynapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically isolated syndrome; however, the effects and fate of autoantibodies in neurons are still unexplored. We found that in vitro exposure of primary hippocampal neurons to patient’s autoantibodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synaptic transmission. These effects were reproduced with a purified SynI antibody and completely absent in SynI knockout neurons. Autoantibodies to SynI are internalized by FcγII/III-mediated endocytosis, interact with endogenous SynI, and promote its sequestration and intracellular aggregation. Neurons exposed to human autoantibodies to SynI display a reduced density of SVs, mimicking the SynI loss-of-function phenotype. Our data indicate that autoantibodies to intracellular antigens such as SynI can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction may contribute to the evolution and progression of autoimmune-mediated neurological diseases positive for SynI autoantibodies.

Brain Organoids: Tiny Mirrors of Human Neurodevelopment and Neurological Disorders

2020 ◽  
pp. 107385842094319 ◽  
Author(s):  
Anuradha Yadav ◽  
Brashket Seth ◽  
Rajnish Kumar Chaturvedi
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Human Brain ◽  
Neurological Disorders ◽  
3D Model ◽  
Neurological Diseases ◽  
Circuit Complexity ◽  
Model Systems ◽  
Neuronal Circuitry ◽  
Human Brain Development

Unravelling the complexity of the human brain is a challenging task. Nowadays, modern neurobiologists have developed 3D model systems called “brain organoids” to overcome the technical challenges in understanding human brain development and the limitations of animal models to study neurological diseases. Certainly like most model systems in neuroscience, brain organoids too have limitations, as these minuscule brains lack the complex neuronal circuitry required to begin the operational tasks of human brain. However, researchers are hopeful that future endeavors with these 3D brain tissues could provide mechanistic insights into the generation of circuit complexity as well as reproducible creation of different regions of the human brain. Herein, we have presented the contemporary state of brain organoids with special emphasis on their mode of generation and their utility in modelling neurological disorders, drug discovery, and clinical trials.

scholarly journals Social preference is maintained in mice with impaired startle reflex and glutamate/D-serine imbalance induced by chronic cerebral toxoplasmosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariana Acquarone ◽  
A. Poleto ◽  
A. F. Perozzo ◽  
P. F. R. Gonçalves ◽  
R. Panizzutti ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Social Preference ◽  
Neurological Diseases ◽  
Motor Impairment ◽  
Chronic Phase ◽  
Neuropsychiatric Disorders ◽  
Cerebral Toxoplasmosis ◽  
Startle Amplitude ◽  
The Central Nervous System

AbstractToxoplasma gondii is an opportunistic protozoan pathogen with a wide geographic distribution. The chronic phase of toxoplasmosis is often asymptomatic in humans and is characterized by tissue cysts throughout the central nervous system and muscle cells. T. gondii and other pathogens with tropism for the central nervous system are considered risk factors in the etiology of several neuropsychiatric disorders, such as schizophrenia and bipolar disorder, besides neurological diseases. Currently, it is known that cerebral toxoplasmosis increases dopamine levels in the brain and it is related to behavioral changes in animals and humans. Here we evaluate whether chronic T. gondii infection, using the cystogenic ME-49 strain, could induce behavioral alterations associated with neuropsychiatric disorders and glutamatergic neurotransmission dysfunction. We observed that the startle amplitude is reduced in the infected animals as well as glutamate and D-serine levels in prefrontal cortical and hippocampal tissue homogenates. Moreover, we did not detect alterations in social preference and spontaneous alternation despite severe motor impairment. Thus, we conclude that behavioral and cognitive aspects are maintained even though severe neural damage is observed by chronic infection of C57Bl/6 mice with the ME-49 strain.

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