scholarly journals Impaired inhibitory control of cortical synchronization in fragile X syndrome

2011 ◽  
Vol 106 (5) ◽  
pp. 2264-2272 ◽  
Author(s):  
Scott M. Paluszkiewicz ◽  
Jose Luis Olmos-Serrano ◽  
Joshua G. Corbin ◽  
Molly M. Huntsman
Keyword(s):  
Fragile X Syndrome ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Synaptic Inhibition ◽  
Cortical Interneuron ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Functional Defect

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

scholarly journals Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome

2014 ◽  
Vol 11 (1) ◽  
pp. 110 ◽  
Author(s):  
Milo Careaga ◽  
Tamanna Noyon ◽  
Kirin Basuta ◽  
Judy Van de Water ◽  
Flora Tassone ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Immune Dysfunction ◽  
Metabotropic Glutamate ◽  
Group I

Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome

2015 ◽  
Vol 20 ◽  
pp. 124-134 ◽  
Author(s):  
Sebastian H Scharf ◽  
Georg Jaeschke ◽  
Joseph G Wettstein ◽  
Lothar Lindemann
Keyword(s):  
Fragile X Syndrome ◽  
Glutamate Receptor ◽  
Drug Target ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Metabotropic Glutamate Receptor 5 ◽  
Metabotropic Glutamate

scholarly journals Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study

2021 ◽  
Vol 22 (6) ◽  
pp. 2863
Author(s):  
James Robert Brašić ◽  
Ayon Nandi ◽  
David S. Russell ◽  
Danna Jennings ◽  
Olivier Barret ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X Syndrome ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Receptor Subtype ◽  
Metabotropic Glutamate

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR5 expression provide conflicting findings about the nature of dysregulation of cerebral mGluR5 pathways in subtypes of ASD. The demonstration of reduced mGluR5 expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR5 expression in ASD. We aimed to (A) compare and contrast mGluR5 expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a novel, specific mGluR5 PET ligand to quantitatively measure the density and the distribution of mGluR5s in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR5 expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR5 expression in clinical trials of individuals with IASD and FXS and related conditions.

scholarly journals Pathological Plasticity in Fragile X Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Brandon S. Martin ◽  
Molly M. Huntsman
Keyword(s):  
Fragile X Syndrome ◽  
Neuronal Networks ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Single Gene ◽  
Critical Periods ◽  
Metabotropic Glutamate ◽  
Early Developmental ◽  
Homeostatic Mechanisms ◽  
Developmental Pathology

Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS), disruption in the function of a single gene,FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.

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