Increased Training Intensity Induces Proper Membrane Localization of Actin Remodeling Proteins in the Hippocampus Preventing Cognitive Deficits: Implications for Fragile X Syndrome

2017 ◽  
Vol 55 (6) ◽  
pp. 4529-4542 ◽  
Author(s):  
L. A. Martinez ◽  
Maria Victoria Tejada-Simon
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Membrane Localization ◽  
Training Intensity ◽  
Actin Remodeling

scholarly journals 116.1 GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Some Cognitive Deficits in a Fragile X Syndrome Mouse Model

2017 ◽  
Vol 43 (suppl_1) ◽  
pp. S62-S62
Author(s):  
Steven Siegel ◽  
Dunan Sinclair ◽  
Mitsuyuki Matsumoto ◽  
Robert Featherstone ◽  
Olya Melnechenko ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Neural Oscillations

scholarly journals Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

2022 ◽  
Author(s):  
Sahar Javadi ◽  
Yue Li ◽  
Jie Shen ◽  
Lucy Zhao ◽  
Yao Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Therapeutic Effects ◽  
Mature Adult ◽  
Mature Adults ◽  
Deficient Mice

Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

scholarly journals Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

2017 ◽  
Author(s):  
Dino Dvorak ◽  
Basma Radwan ◽  
Fraser T. Sparks ◽  
Zoe Nicole Talbot ◽  
André A. Fenton
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Pyramidal Cell ◽  
Fragile X ◽  
Avoidance Task ◽  
Cognitive Variables ◽  
Wild Type ◽  
Cognitive Inflexibility ◽  
Place Avoidance ◽  
Shock Zone

ABSTRACTBehavior is used to assess memory and cognitive deficits in animals like Fmrl-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal CA1 hippocampus. During a shocked-place avoidance task, slow gamma (SG: 30-50 Hz) dominates mid-frequency gamma (MG: 70-90 Hz) oscillations 2-3 seconds before successful avoidance, but not failures. Wild-type but not Fmrl-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdominance) decrease in wild-type but not in cognitively inflexible Fmrl-null mice. During SGdominance, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, wild-type ensembles represent distant locations near the currently-correct shock zone but Fmrl-null ensembles represent the formerly-correct zone. These findings indicate that recollection occurs when CA1 slow gamma dominates mid-frequency gamma, and that accurate recollection of inappropriate memories explains Fmrl-null cognitive inflexibility.

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

2019 ◽  
Vol 70 (1) ◽  
pp. 167-181 ◽  
Author(s):  
Ilse Gantois ◽  
Jelena Popic ◽  
Arkady Khoutorsky ◽  
Nahum Sonenberg
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Neurological Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Cellular Models ◽  
The Us ◽  
Mental Retardation Protein ◽  
Drug Treatments ◽  
Core Symptoms

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

FMRP Modulates Activity-Dependent Spine Plasticity by Binding Cofilin1 mRNA and Regulating Localization and Local Translation

2019 ◽  
Vol 29 (12) ◽  
pp. 5204-5216 ◽  
Author(s):  
Jonas Feuge ◽  
Franziska Scharkowski ◽  
Kristin Michaelsen-Preusse ◽  
Martin Korte
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Treatment Strategies ◽  
Actin Dynamics ◽  
Actin Remodeling ◽  
Dendritic Spine Morphology ◽  
Novel Treatment Strategies ◽  
Activity Dependent ◽  
Spine Plasticity

Abstract Multiple variants of intellectual disability, e.g., the Fragile X Syndrome are associated with alterations in dendritic spine morphology, thereby pointing to dysregulated actin dynamics during development and processes of synaptic plasticity. Surprisingly, although the necessity of spine actin remodeling was demonstrated repeatedly, the importance and precise role of actin regulators is often undervalued. Here, we provide evidence that structural and functional plasticity are severely impaired after NMDAR-dependent LTP in the hippocampus of Fmr1 KO mice. We can link these defects to an aberrant activity-dependent regulation of Cofilin 1 (cof1) as activity-dependent modulations of local cof1 mRNA availability, local cof1 translation as well as total cof1 expression are impaired in the absence of FMRP. Finally, we can rescue activity-dependent structural plasticity in KO neurons by mimicking the regulation of cof1 observed in WT cells, thereby illustrating the potential of actin modulators to provide novel treatment strategies for the Fragile X Syndrome.

scholarly journals MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome

2016 ◽  
Vol 8 (336) ◽  
pp. 336ra61-336ra61 ◽  
Author(s):  
Yue Li ◽  
Michael E. Stockton ◽  
Ismat Bhuiyan ◽  
Brian E. Eisinger ◽  
Yu Gao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X

scholarly journals Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice

2018 ◽  
Vol 115 (41) ◽  
pp. E9707-E9716 ◽  
Author(s):  
Jingqi Yan ◽  
Morgan W. Porch ◽  
Brenda Court-Vazquez ◽  
Michael V. L. Bennett ◽  
R. Suzanne Zukin
Keyword(s):  
Synaptic Plasticity ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Hippocampal Neurons ◽  
Fragile X ◽  
Expression System ◽  
Mammalian Target Of Rapamycin ◽  
Autophagic Flux ◽  
Protein Activation ◽  
Spine Structure

Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (Fmr1-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway. However, a role for autophagy in the pathophysiology of FXS is, as yet, unclear. Here we show that autophagic flux, a functional readout of autophagy, and biochemical markers of autophagy are down-regulated in hippocampal neurons of fragile X mice. We further show that enhanced activity of mammalian target of rapamycin complex 1 (mTORC1) and translocation of Raptor, a defining component of mTORC1, to the lysosome are causally related to reduced autophagy. Activation of autophagy by delivery of shRNA to Raptor directly into the CA1 of living mice via the lentivirus expression system largely corrects aberrant spine structure, synaptic plasticity, and cognition in fragile X mice. Postsynaptic density protein (PSD-95) and activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), proteins implicated in spine structure and synaptic plasticity, respectively, are elevated in neurons lacking fragile X mental retardation protein. Activation of autophagy corrects PSD-95 and Arc abundance, identifying a potential mechanism by which impaired autophagy is causally related to the fragile X phenotype and revealing a previously unappreciated role for autophagy in the synaptic and cognitive deficits associated with fragile X syndrome.

scholarly journals Defective memory engram reactivation underlies impaired fear memory recall in Fragile X syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jie Li ◽  
Rena Y Jiang ◽  
Kristin L Arendt ◽  
Yu-Tien Hsu ◽  
Sophia R Zhai ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Fear Memory ◽  
Enriched Environment ◽  
Memory Recall ◽  
Behavioral Learning ◽  
Functional Deficits ◽  
Network Activation ◽  
Memory Engram

Fragile X syndrome (FXS) is an X chromosome-linked disease associated with severe intellectual disabilities. Previous studies using the Fmr1 knockout (KO) mouse, an FXS mouse model, have attributed behavioral deficits to synaptic dysfunctions. However, how functional deficits at neural network level lead to abnormal behavioral learning remains unexplored. Here, we show that the efficacy of hippocampal engram reactivation is reduced in Fmr1 KO mice performing contextual fear memory recall. Experiencing an enriched environment (EE) prior to learning improved the engram reactivation efficacy and rescued memory recall in the Fmr1 KO mice. In addition, chemogenetically inhibiting EE-engaged neurons in CA1 reverses the rescue effect of EE on memory recall. Thus, our results suggest that inappropriate engram reactivation underlies cognitive deficits in FXS, and enriched environment may rescue cognitive deficits by improving network activation accuracy.

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