Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by silence of the fmr1 gene and the deficiency of Fragile X mental retardation protein (FMRP). Patients present neuronal alterations that lead to severe intellectual disability and altered sleep rhythms. However, the neural circuit mechanisms underlying FXS remain unclear. Previous studies have suggested that metabolic glutamate and gamma-aminobutyric acid (GABA) receptors/circuits are two counter-balanced factors involved in FXS pathophysiology. More and more studies demonstrated that attenuated GABAergic circuits in the absence of FMRP are critical for abnormal progression of FXS. Here, we reviewed the changes of GABA neural circuits that were attributed to intellectual-deficient FXS, from several aspects including deregulated GABA metabolism, decreased expressions of GABA receptor subunits, and impaired GABAergic neural circuits. Furthermore, the activities of GABA neural circuits are modulated by circadian rhythm of FMRP metabolism and reviewed the abnormal condition of FXS mice or patients.

A critical residue in the α1M2–M3 linker regulating mammalian GABAA receptor pore gating by diazepam

“…The most prominent subtype at synapses is comprised of α 1 , β n , and γ 2 subunits ( Sieghart and Sperk, 2002 ). GABA A Rs provide a critical balance with excitatory signaling for normal neural function, and not surprisingly, their dysfunction is related to disorders such as epilepsy, autism spectrum disorder, intellectual disability, schizophrenia, and neurodevelopmental disorders such as fragile X syndrome ( Hernandez and Macdonald, 2019 ; Gao et al, 2018 ; Mahdavi et al, 2018 ; Braat and Kooy, 2015 ; Vien et al, 2015 ; Rudolph and Möhler, 2014 ; Limon et al, 2012 ; Ramamoorthi and Lin, 2011 ; Solís-Añez et al, 2007 ). Although pharmacological manipulation of GABA A Rs is a powerful approach to tuning neural signaling, the rational design of novel therapies is challenged by a lack of understanding of the molecular mechanism by which drugs such as BZDs modulate channel behavior.…”

Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour

“…Large-scale forms of plasticity such as homeostatic plasticity have also been reported to be impaired in Fmr1- KO mice [219,220]. Other than glutamatergic synaptic impairments, Fmr1- KO mice further show reduced dopamine- [221] and GABAR-mediated signalling, and the number of GABARs were altered in Fmr1- KO mice [222]. These alterations in GABAR cause aberrant GABAR-mediated signalling, contributing to an altered E/I balance [223–226].…”

Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on?

“…A temporal deviation from this switch leads to the persistence of immature GABAergic features in the adult brain, which perturb the operation of well-developed functional networks 22 . According to its functional importance during development, GABA is implicated in a number of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) 23 , Fragile X 24 , Rett syndrome 25 , 26 , Down syndrome 27 , and schizophrenia 28 . In this review, we discuss experimental evidence indicating that developmental GABA switch is largely influenced by environmental stimuli, thus possibly representing a central link that translates early-life environmental hits into behavioral changes in the adult.…”