scholarly journals Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

2020 ◽  
Author(s):  
Jelena Scekic-Zahirovic ◽  
Inmaculada Sanjuan-Ruiz ◽  
Vanessa Kan ◽  
Salim Megat ◽  
Pierre De Rossi ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Rna Binding ◽  
Gene Mutations ◽  
Neuronal Loss ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Behavioral Alterations ◽  
Behavioral Abnormalities ◽  
Cytoplasmic Accumulation

AbstractGene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

scholarly journals Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jelena Scekic-Zahirovic ◽  
Inmaculada Sanjuan-Ruiz ◽  
Vanessa Kan ◽  
Salim Megat ◽  
Pierre De Rossi ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Neuronal Activity ◽  
Rna Binding ◽  
Gene Mutations ◽  
Neuronal Loss ◽  
Progressive Increase ◽  
Behavioral Alterations ◽  
Behavioral Abnormalities ◽  
Morphological Defects

AbstractGene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization.

scholarly journals Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Dávid Nagy ◽  
Lauren Herl Martens ◽  
Liza Leventhal ◽  
Angela Chen ◽  
Craig Kelley ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Loss Of Function ◽  
Behavioral Alterations ◽  
Response Latencies ◽  
Reward Seeking ◽  
Behavioral Abnormalities ◽  
Age Dependent

Abstract Background Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. Methods The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic—medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.5 months. Results Electrophysiological recordings identified a clear age-dependent deficit in the thalamocortical circuit. Both heterozygous and homozygous mice exhibited impaired input-output relationships and paired-pulse depression, but evoked response latencies were only prolonged in heterozygotes. Furthermore, we demonstrate firstly an abnormal reward-seeking/processing behavior in the homozygous mice which correlates with previously reported neuroinflammation. Conclusion Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia.

scholarly journals Eukaryotic initiation factor EIF-3.G augments mRNA translation efficiency to regulate neuronal activity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Stephen M Blazie ◽  
Seika Takayanagi-Kiya ◽  
Katherine M McCulloch ◽  
Yishi Jin
Keyword(s):  
Neuronal Activity ◽  
Rna Binding ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Translation Efficiency ◽  
Dependent Manner ◽  
C Elegans ◽  
Protein Levels ◽  
Neuronal Protein

The translation initiation complex eIF3 imparts specialized functions to regulate protein expression. However, understanding of eIF3 activities in neurons remains limited despite widespread dysregulation of eIF3 subunits in neurological disorders. Here, we report a selective role of the C. elegans RNA-binding subunit EIF-3.G in shaping the neuronal protein landscape. We identify a missense mutation in the conserved Zinc-Finger (ZF) of EIF-3.G that acts in a gain-of-function manner to dampen neuronal hyperexcitation. Using neuron type-specific seCLIP, we systematically mapped EIF-3.G-mRNA interactions and identified EIF-3.G occupancy on GC-rich 5′UTRs of a select set of mRNAs enriched in activity-dependent functions. We demonstrate that the ZF mutation in EIF-3.G alters translation in a 5′UTR dependent manner. Our study reveals an in vivo mechanism for eIF3 in governing neuronal protein levels to control neuronal activity states and offers insights into how eIF3 dysregulation contributes to neuronal disorders.

scholarly journals Differential contribution of excitatory and inhibitory neurons in shaping neurovascular coupling in different epileptic neural states

2020 ◽  
pp. 0271678X2093407
Author(s):  
Hyun-Kyoung Lim ◽  
Nayeon You ◽  
Sungjun Bae ◽  
Bok-Man Kang ◽  
Young-Min Shon ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Field Potential ◽  
Neurovascular Coupling ◽  
Vessel Diameter ◽  
Functional Brain Imaging ◽  
Activity Level ◽  
Inhibitory Neurons ◽  
Activity Levels ◽  
Ictal Activity

Understanding the neurovascular coupling (NVC) underlying hemodynamic changes in epilepsy is crucial to properly interpreting functional brain imaging signals associated with epileptic events. However, how excitatory and inhibitory neurons affect vascular responses in different epileptic states remains unknown. We conducted real-time in vivo measurements of cerebral blood flow (CBF), vessel diameter, and excitatory and inhibitory neuronal calcium signals during recurrent focal seizures. During preictal states, decreases in CBF and arteriole diameter were closely related to decreased γ-band local field potential (LFP) power, which was linked to relatively elevated excitatory and reduced inhibitory neuronal activity levels. Notably, this preictal condition was followed by a strengthened ictal event. In particular, the preictal inhibitory activity level was positively correlated with coherent oscillating activity specific to inhibitory neurons. In contrast, ictal states were characterized by elevated synchrony in excitatory neurons. Given these findings, we suggest that excitatory and inhibitory neurons differentially contribute to shaping the ictal and preictal neural states, respectively. Moreover, the preictal vascular activity, alongside with the γ-band, may reflect the relative levels of excitatory and inhibitory neuronal activity, and upcoming ictal activity. Our findings provide useful insights into how perfusion signals of different epileptic states are related in terms of NVC.

scholarly journals Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 453 ◽  
Author(s):  
Sung-Tzu Liang ◽  
Gilbert Audira ◽  
Stevhen Juniardi ◽  
Jung-Ren Chen ◽  
Yu-Heng Lai ◽  
...  
Keyword(s):  
Telomerase Activity ◽  
In Vivo Model ◽  
Loss Of Function ◽  
Behavioral Alterations ◽  
Fish Model ◽  
Behavioral Abnormalities ◽  
Vertebrate Model ◽  
And Behavior ◽  
External Stimuli

Aging is a natural process that internal gene control and external stimuli mediate. Clinical data pointed out that homozygotic or heterozygotic mutation in the pyrroline-5-carboxylate reductase 1 (PYCR1) gene in humans caused cutis laxa (ARCL) disease, with progeroid appearance, lax and wrinkled skin, joint laxity, osteopenia, and mental retardation phenotypes. In this study, we aimed to generate pycr1 knockout (KO) zebrafish and carried out biochemical characterizations and behavior analyses. Marked apoptosis and senescence were detected in pycr1 KO zebrafish, which started from embryos/larvae stage. Biochemical assays showed that adult pycr1 KO fish have significantly reduced proline and extracellular matrix contents, lowered energy, and diminished superoxide dismutase (SOD) and telomerase activity when compared to the wild type fish, which suggested the pycr1 KO fish may have dysfunction in mitochondria. The pycr1 KO fish were viable; however, displayed progeria-like phenotype from the 4 months old and reach 50% mortality around six months old. In adult stage, we found that pycr1 KO fish showed reduced locomotion activity, aggression, predator avoidance, social interaction interest, as well as dysregulated color preference and circadian rhythm. In summary, we have identified multiple behavioral alterations in a novel fish model for aging with pycr1 gene loss-of-function by behavioral tests. This animal model may not only provide a unique vertebrate model to screen potential anti-aging drugs in the future, but also be an excellent in vivo model towards a better understanding of the corresponding behavioral alterations that accompany aging.

Evaluation of the In Vivo Acute Toxicity and In Vitro Hemolytic and Immunomodulatory Activities of the Moringa oleifera Flower Trypsin Inhibitor (MoFTI)

2020 ◽  
Vol 27 ◽  
Author(s):  
Leydianne Leite de Siqueira Patriota ◽  
Dayane Kelly Dias do Nascimento Santos ◽  
Bárbara Rafaela da Silva Barros ◽  
Lethícia Maria de Souza Aguiar ◽  
Yasmym Araújo Silva ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Trypsin Inhibitor ◽  
Hemolytic Activity ◽  
Moringa Oleifera ◽  
Biological Activities ◽  
Hematological Parameters ◽  
Behavioral Alterations ◽  
Female Mice

Background: Protease inhibitors have been isolated from plants and present several biological activities, including immunomod-ulatory action. Objective: This work aimed to evaluate a Moringa oleifera flower trypsin inhibitor (MoFTI) for acute toxicity in mice, hemolytic activity on mice erythrocytes and immunomodulatory effects on mice splenocytes. Methods: The acute toxicity was evaluated using Swiss female mice that received a single dose of the vehicle control or MoFTI (300 mg/kg, i.p.). Behavioral alterations were observed 15–240 min after administration, and survival, weight gain, and water and food consumption were analyzed daily. Organ weights and hematological parameters were analyzed after 14 days. Hemolytic activity of MoFTI was tested using Swiss female mice erythrocytes. Splenocytes obtained from BALB/c mice were cultured in the absence or presence of MoFTI for the evaluation of cell viability and proliferation. Mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were also determined. Furthermore, the culture supernatants were analyzed for the presence of cytokines and nitric oxide (NO). Results: MoFTI did not cause death or any adverse effects on the mice except for abdominal contortions at 15–30 min after administration. MoFTI did not exhibit a significant hemolytic effect. In addition, MoFTI did not induce apoptosis or necrosis in splenocytes and had no effect on cell proliferation. Increases in cytosolic and mitochondrial ROS release, as well as ΔΨm reduction, were observed in MoFTI-treated cells. MoFTI was observed to induce TNF-α, IFN-γ, IL-6, IL-10, and NO release. Conclusion: These results contribute to the ongoing evaluation of the antitumor potential of MoFTI and its effects on other immunological targets.

scholarly journals The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Saikat Bhattacharya ◽  
Michaella J. Levy ◽  
Ning Zhang ◽  
Hua Li ◽  
Laurence Florens ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Rna Binding ◽  
Mrna Processing ◽  
Key Factors ◽  
Pol Ii ◽  
Mrna Transcripts ◽  
Hnrnp Protein ◽  
Processing Factors

AbstractHeterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that are involved in key processes such as RNA splicing and transcription. One such hnRNP protein, hnRNP L, regulates alternative splicing (AS) by binding to pre-mRNA transcripts. However, it is unclear what factors contribute to hnRNP L-regulated AS events. Using proteomic approaches, we identified several key factors that co-purify with hnRNP L. We demonstrate that one such factor, the histone methyltransferase SETD2, specifically interacts with hnRNP L in vitro and in vivo. This interaction occurs through a previously uncharacterized domain in SETD2, the SETD2-hnRNP Interaction (SHI) domain, the deletion of which, leads to a reduced H3K36me3 deposition. Functionally, SETD2 regulates a subset of hnRNP L-targeted AS events. Our findings demonstrate that SETD2, by interacting with Pol II as well as hnRNP L, can mediate the crosstalk between the transcription and the splicing machinery.

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