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

Reymundo Lozano, Emma B. Hare, Randi J Hagerman

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 defcits 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.

Original languageEnglish (US)
Pages (from-to)1769-1779
Number of pages11
JournalNeuropsychiatric Disease and Treatment
Volume10
DOIs
StatePublished - Sep 16 2014

Fingerprint

Fragile X Syndrome
Autistic Disorder
gamma-Aminobutyric Acid
Metabotropic Glutamate Receptors
GABA Receptors
Anxiety
Therapeutics
Intellectual Disability
Fragile X Mental Retardation Protein
Riluzole
Vigabatrin
Neurobiology
Brain
Genes
Seizures
Safety

Keywords

  • Arbaclofen
  • Autism
  • Gamma-aminobutyric acid (GABA) system
  • Ganax-olone
  • Targeted treatments

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Modulation of the GABAergic pathway for the treatment of fragile X syndrome. / Lozano, Reymundo; Hare, Emma B.; Hagerman, Randi J.

In: Neuropsychiatric Disease and Treatment, Vol. 10, 16.09.2014, p. 1769-1779.

Research output: Contribution to journalArticle

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