title: Impaired inhibitory control of cortical synchronization in fragile X syndrome.
abstract: 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.
authors.affiliation: Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Paluszkiewicz
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Olmos-Serrano
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Corbin
authors.forename: Molly M
authors.initials: MM
authors.lastname: Huntsman
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D003344:Cortical Synchronization / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D007395:Interneurons / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D009924:Organ Culture Techniques; D010641:Phenotype; D017966:Pyramidal Cells / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D013003:Somatosensory Cortex / Q000166:cytology / Q000503:physiopathology*; D013004:Somatostatin / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D018094:Receptors, Metabotropic Glutamate; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; C497684:Fmr1 protein, mouse; C104077:metabotropic glutamate receptor type 1; C010117:3,4-dihydroxyphenylglycol