Fragile X Syndrome: The GABAergic System and Circuit Dysfunction

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, sensory hypersensitivity, and high incidences of autism spectrum disorders and epilepsy. These phenotypes are suggestive of defects in neural circuit development and imbalances in excitatory glutamatergic and inhibitory GABAergic neurotransmission. While alterations in excitatory synapse function and plasticity are well-established in Fmr1 knockout (KO) mouse models of FXS, a number of recent electrophysiological and molecular studies now identify prominent defects in inhibitory GABAergic transmission in behaviorally relevant forebrain regions such as the amygdala, cortex, and hippocampus. In this review, we summarize evidence for GABAergic system dysfunction in FXS patients and Fmr1 KO mouse models alike. We then discuss some of the known developmental roles of GABAergic signaling, as well as the development and refinement of GABAergic synapses as a framework for understanding potential causes of mature circuit dysfunction. Finally, we highlight the GABAergic system as a relevant target for the treatment of FXS.

Psychosis and catatonia in fragile X: Case report and literature review

“…The lack of FMRP will cause down-regulation of the gammaamino butyric acid (GABA) A and B receptors and up-regulation of metabotropic glutamate receptor 5 (mGluR5) throughout the brain (22)(23)(24). FMRP is highly expressed in neurons and FMRP is critical for synaptic plasticity (25,26).…”

Bryostatin-1 Restores Hippocampal Synapses and Spatial Learning and Memory in Adult Fragile X Mice

“…Its lack results in an overactivity of the mGluRs, a decreased GABAergic system or delayed developmental switch in GABA polarity (D'Hulst et al, 2006;Olmos-Serrano et al, 2010;He et al, 2014), and an elevated activity of GSK-3b . Potential therapeutics, therefore, include mGluR inhibitors (Vinueza Veloz et al, 2012), GABAergic enhancers (D'Hulst andKooy, 2007;Olmos-Serrano et al, 2010;Paluszkiewicz et al, 2011;Heulens et al, 2012), and inhibitors of GSK-3b (Yuskaitis et al, 2010;Guo et al, 2012). Because intellectual ability, as well as retardation (Wang et al, 2012) involves multiple players in signal processing, bryostatin-1-like agents, for their multitargeting actions, may represent a more effective class of therapeutics than agents that target a single factor in this complex pathologic process (Vislay et al, 2013).…”

Gephyrin: a master regulator of neuronal function?

“…Rather, it induces alterations in the neuronal networks that are established during these critical periods 156 , possibly due to impaired gephyrin clustering and downstream signalling. Taken from a broader perspective, a major implication of the complex regulation of gephyrin clustering is that mutations and disease mechanisms interfering with the proteins and signalling cascades that regulate gephyrin clustering have the potential to perturb GABAergic transmission during critical periods of brain development 158 , and thereby to contribute to the pathophysiology of neurodevelopmental disorders 5,6,159,160 . Transcription factors, such as NPAS4, have been identified that regulate GABAergic synaptogenesis by controlling the expression of activitydependent genes, and this finding may represent a potential mechanism for such perturbations 161 …”