Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic 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.

Download Full-text

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

10.1101/2020.06.09.141556 ◽

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.

Download Full-text

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

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0540-x ◽

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.

Download Full-text

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

Molecular Psychiatry ◽

10.1038/s41380-020-0653-4 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2712-2727 ◽

Cited By ~ 10

Author(s):

Amber J. Zimmerman ◽

Alexander K. Hafez ◽

Stephen K. Amoah ◽

Brian A. Rodriguez ◽

Michela Dell’Orco ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Frontal Cortex ◽

Cognitive Flexibility ◽

Rna Binding ◽

Age Of Onset ◽

Psychiatric Disease ◽

Mammalian Brain ◽

Neuronal Cultures

Abstract Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.

Download Full-text

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

eLife ◽

10.7554/elife.68336 ◽

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.

Download Full-text

Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities

Cells ◽

10.3390/cells8050453 ◽

2019 ◽

Vol 8 (5) ◽

pp. 453 ◽

Cited By ~ 5

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.

Download Full-text

Faculty Opinions recommendation of In vivo imaging of neuronal activity by targeted expression of a genetically encoded probe in the mouse.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006862.213445 ◽

2004 ◽

Author(s):

Lawrence C Katz

Keyword(s):

Neuronal Activity ◽

In Vivo Imaging ◽

Targeted Expression

Download Full-text

Faculty Opinions recommendation of Neuronal activity related to reward value and motivation in primate frontal cortex.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005518.212417 ◽

2004 ◽

Author(s):

Douglas Munoz

Keyword(s):

Frontal Cortex ◽

Neuronal Activity ◽

Reward Value

Download Full-text

Faculty Opinions recommendation of Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718004235.793475796 ◽

2013 ◽

Author(s):

Long-Jun Wu ◽

Ukpong B Eyo

Keyword(s):

Neuronal Activity ◽

Reciprocal Regulation

Download Full-text

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

Protein and Peptide Letters ◽

10.2174/0929866527999201113105858 ◽

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.

Download Full-text