Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome

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.

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

10.1101/152488 ◽

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.

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Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

Annual Review of Medicine ◽

10.1146/annurev-med-081117-041238 ◽

2019 ◽

Vol 70 (1) ◽

pp. 167-181 ◽

Cited By ~ 19

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.

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