Targeting the endocannabinoid system in the treatment of fragile X syndrome

Busquets-García, Arnau; Gomis-González, María; Guegan, Thomas; Agustín-Pavón, Carmen; Pastor, Antoni; Mato, Susana; Pérez-Samartı́n, Alberto; Matute, Carlos; Torre, Rafael de la; Dierssen, Mara; Maldonado, Rafaël; Ozaita, Andrés

doi:10.1038/nm.3127

Cited by 201 publications

(181 citation statements)

References 33 publications

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“…For a more extensive review of Fmr1 knockout mice behavioral phenotypes see [180]. Behavior: social dominance [119]; sociability [132] Cognition: object recognition (chronic, not acute) [121]; fear conditioning [120]; associative motor learning (acute) [133]; inhibitory avoidance (chronic and acute) [129,133]; extinction memory (chronic) [129] LTP deficits in the amygdala and hippocampus (bath application) [128,134]; LTD (bath application) [135] startle response, † rotarod performance [131]; object recognition (acute) [121,134]; coordinate and categorical tasks (acute) [134]; analgesic response [121] mGlu5 NAMs used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…• MPEP [43,62,63,97,123,126,128,130,131,134] • MTEP [121] • Fenobam [124,126,133] • AFQ056 [119,125,127,132] CTEP [120,129] mGlu1 Genetic (het) Hyperexcitability: locomotor activity [118] Macro-orchidism, PPI, startle response, AGS, social interaction [118] Pharm Hyperexcitability: AGS (partially) [131] Startle response, rotarod [131] Muscarinic R (subtypes M1 and M4) Genetic (het) Plasticity and hyperexcitability: analgesic response, startle response (M4) [136] PPI, MB, light-dark transition (anxiety), AGS, macro-orchidism [136] Pharm Plasticity and hyperexcitability: AGS (M1+M4) [137,138] Cognition: passive avoidance (M4) [138] Passive avoidance (M1) [137] Group II mGlu N/A GSK3β antagonists used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…Clinical trials using this approach have, so far, been unsuccessful in showing an improvement of FXS-associated phenotypes in humans, possibly because only behavioral phenotypes were addressed in older patients [194]. Of note, recent studies in the mouse model showed that chronic treatment with mGlu5 NAMs is necessary to improve memory deficits [120,121,129], suggesting that prolonged treatment in patients may also be beneficial. Notably, targeting mGlu5 seems to be more efficient in rescuing phenotypes in the FXS mouse model than targeting other G-coupled receptors that were also shown to be dysregulated in FXS [217], such as mGlu1 or muscarinic receptors M1 and M4 [118,131,[136][137][138].…”

Section: Neurotransmitter Receptors Versus Intracellular Signaling Anmentioning

confidence: 99%

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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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Section: Macro-orchidismmentioning

confidence: 99%

Section: Macro-orchidismmentioning

confidence: 99%

Section: Neurotransmitter Receptors Versus Intracellular Signaling Anmentioning

confidence: 99%

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

et al. 2015

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“…In the first study addressing eCB system in FXS, it has been reported that the ablation fmr1 gene causes a dysfunctional 2-AG metabolism, with increasing DAGL and MAGL activities in the striatum of fmr1 -/-mutants, but unaltered striatal 2-AG levels [100]. According to a more recent study [101], stimulation of 2-AG signaling could be a useful treatment for mitigating FXS symptoms because it is able to normalize synaptic activity through type I metabotropic glutamate activation; additionally, genetic or pharmacological attenuation of CB 1 -dependent signal transduction and blockade of the mammalian target of rapamycin pathway might provide alternative strategies to treat autistic patients [102].…”

Section: Alterations Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the Bendocannabinoid (eCB) system^, a rather complex ensemble of lipid signals (Bendocannabinoids^), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.Key Words Autism spectrum disorder . endocannabinoid system . fragile X syndrome . metabolic regulation . reward system The Endocannabinoid SystemTwenty-five years after the cloning and expression of a complementary DNA that encoded a G protein-coupled receptor, named type-1 cannabinoid (CB 1 ) receptor [1], there is a good deal of information on the main components of the so-called Bendocannabinoid (eCB) system^, as well as on its role in controlling cannabinergic signaling in human health and disease [2][3][4]. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most active eCBs as yet identified, although this family of bioactive lipids includes other arachidonic acid (AA) derivatives with cannabimimetic properties (i.e., noladin ether, virodhamine, N-arachidonoyldopamine, to name but a few). The classical dogma that eCBs are synthesized and released Bon demand^upon (patho)physiological stimuli has been recently revisited on the basis of unexpected evidence for intracellular reservoirs and transporters of eCBs. These new entities have been shown to drive intracellular trafficking of eCBs, adding a new dimension to the regulation of their biological activity [5]. To date, several metabolic routes have B. Chakrabarti, A. Persico and N. Battista are equal first authors.

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“…Interestingly, a recent study showed that BDNF delivered after disease onset reversed pathology in an AD model (137). BDNF administration in the entorhinal cortex compensated for genetic, molecular and behavioral parameters of age-related mechanisms (179,187), gene therapy (19,(188)(189)(190)(191)(192)(193) and genetic depletion (6,9,194,195). These approaches have shown great efficacy, at least in experimental models, in restoring spine density and memory function.…”

Section: Potential Mediators Of Xbp1 Signaling In Neuronsmentioning

confidence: 99%

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

Cissé

Duplan

Checler

2016

Mol Med

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X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor that was isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein that regulates many physiological functions, including the immune system, inflammatory responses and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays an important role in pathological settings, since its activity as a transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration and diabetes. Here we provide an overview of recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases, with an emphasis on Alzheimer's disease.

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Targeting the endocannabinoid system in the treatment of fragile X syndrome

Cited by 201 publications

References 33 publications

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

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

Endocannabinoid Signaling in Autism

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

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