Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Reymundo Lozano,1,2 Emma B Hare,1,2 Randi J Hagerman1,2 1MIND Institute, 2Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA Abstract: Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is cau...

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Autores principales:	Lozano R, Hare EB, Hagerman RJ
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2014
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/93aa0c19c4ba410d9e40f0e9d2a11c33
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spelling	oai:doaj.org-article:93aa0c19c4ba410d9e40f0e9d2a11c332021-12-02T02:55:15ZModulation of the GABAergic pathway for the treatment of fragile X syndrome1178-2021https://doaj.org/article/93aa0c19c4ba410d9e40f0e9d2a11c332014-09-01T00:00:00Zhttp://www.dovepress.com/modulation-of-the-gabaergic-pathway-for-the-treatment-of-fragile-x-syn-peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021 Reymundo Lozano,1,2 Emma B Hare,1,2 Randi J Hagerman1,2 1MIND Institute, 2Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA Abstract: Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS. Keywords: gamma-aminobutyric acid (GABA) system, targeted treatments, autism, ganaxolone, arbaclofenLozano RHare EBHagerman RJDove Medical PressarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol 2014, Iss default, Pp 1769-1779 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Lozano R Hare EB Hagerman RJ Modulation of the GABAergic pathway for the treatment of fragile X syndrome
description	Reymundo Lozano,1,2 Emma B Hare,1,2 Randi J Hagerman1,2 1MIND Institute, 2Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA Abstract: Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS. Keywords: gamma-aminobutyric acid (GABA) system, targeted treatments, autism, ganaxolone, arbaclofen
format	article
author	Lozano R Hare EB Hagerman RJ
author_facet	Lozano R Hare EB Hagerman RJ
author_sort	Lozano R
title	Modulation of the GABAergic pathway for the treatment of fragile X syndrome
title_short	Modulation of the GABAergic pathway for the treatment of fragile X syndrome
title_full	Modulation of the GABAergic pathway for the treatment of fragile X syndrome
title_fullStr	Modulation of the GABAergic pathway for the treatment of fragile X syndrome
title_full_unstemmed	Modulation of the GABAergic pathway for the treatment of fragile X syndrome
title_sort	modulation of the gabaergic pathway for the treatment of fragile x syndrome
publisher	Dove Medical Press
publishDate	2014
url	https://doaj.org/article/93aa0c19c4ba410d9e40f0e9d2a11c33
work_keys_str_mv	AT lozanor modulationofthegabaergicpathwayforthetreatmentoffragilexsyndrome AT hareeb modulationofthegabaergicpathwayforthetreatmentoffragilexsyndrome AT hagermanrj modulationofthegabaergicpathwayforthetreatmentoffragilexsyndrome
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Modulation of the GABAergic pathway for the treatment of fragile X syndrome

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