Rescue of fragile X syndrome phenotypes in Fmr1KO mice by a BKCa channel opener molecule

Hébert, Betty; Pietropaolo, Susanna; Même, Sandra; Laudier, Béatrice; Laugeray, Anthony; Doisne, Nicolas; Quartier, Angélique; Lefeuvre, Sandrine; Got, Laurence; Cahard, Dominique; Laumonnier, Frédéric; Crusio, Wim E.; Pichon, Jacques; Menuet, Arnaud; Perche, Olivier; Briault, Sylvain

doi:10.1186/s13023-014-0124-6

Cited by 90 publications

(108 citation statements)

References 54 publications

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“…Given the recent cessation of a number of prominent clinical trials aiming to treat FXS through established mechanistic procedures, we feel it is imperative to continue to investigate other mechanisms of FXS and new therapeutic strategies. Our work, together with previous findings 45 , suggests a strong therapeutic potential for BK Ca channel openers for the treatment of this disorder.…”

Section: Discussionsupporting

confidence: 58%

“…We then tested whether a BK Ca channel opener could correct this defect in another batch of behaviorally naive mice. We used BMS-204352, which has been shown to exhibit good bioavailability in the brain following intraperitoneal delivery 45 . Acute treatment with BMS-204352 (2 mg per kg of body weight) selectively eliminated the sensory hypersensitivity of Fmr1 −/y mice (P < 0.05) without affecting startle response in wild-type mice (Fig.…”

Section: Implication Of Bk Ca Channels In Dendritic Hyperexcitabilitymentioning

confidence: 99%

“…For rescue experiments, mice were treated with either BMS-204352 (Tocris) or vehicle (standard saline solution, 0.9 M NaCl, supplemented with 1.25% DMSO and 1.25% Tween 80). BMS-204352 (2 mg per kg) and vehicle were delivered by intraperitoneal injection 30 min before behavioral testing (as described previously 45 ). All mice in a cohort received either vehicle or BMS-204352.…”

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confidence: 99%

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Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

et al. 2014

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Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

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Section: Discussionsupporting

confidence: 58%

Section: Implication Of Bk Ca Channels In Dendritic Hyperexcitabilitymentioning

confidence: 99%

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confidence: 99%

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Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

et al. 2014

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“…Recent studies have revealed an exciting potential connection between the molecular alterations in FXS and startle habituation mechanisms: it has been shown that FMRP directly interacts with synaptic BK channels, which in turn have been shown to be crucial for short-term habituation (Deng et al, 2013; Hebert et al, 2014; Typlt et al, 2013b; Zhang et al, 2014). Unfortunately, startle habituation is not well studied in humans with FXS or Fmr1 ko mice, however, the allosteric BK channel activator BMS-204352 was shown to reverse behavioural and cellular FXS symptoms in Fmr1 ko mice (Hebert et al, 2014), highlighting the potential of studying sensory filtering mechanisms in animal models for developing pharmaceutical treatments.…”

Section: Sensory Processing In Rodent Models Relevant To Fxs and Asdmentioning

confidence: 99%

Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

Sinclair

Oranje

Razak

et al. 2017

Neuroscience & Biobehavioral Reviews

159

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Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics.

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“…Of note, a recent study has identified a potential neuronal correlate of hyperarousal in the somatosensory cortex of Fmr1 KO mice that was rescued pharmacologically using a BK CA channel opener [98]. The same BK CA activator has been used previously to rescue behavioral impairments in the FXS mouse model [166], suggesting that neuronal network hyperexcitability is a useful phenotype to evaluate therapeutic strategies in FXS.…”

Section: Macro-orchidismmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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Rescue of fragile X syndrome phenotypes in Fmr1KO mice by a BKCa channel opener molecule

Cited by 90 publications

References 54 publications

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

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