title: Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome.
abstract: Despite the pronounced neurological deficits associated with mental retardation and autism, it is unknown if altered neocortical circuit function occurs in these prevalent disorders. Here we demonstrate specific alterations in local synaptic connections, membrane excitability, and circuit activity of defined neuron types in sensory neocortex of the mouse model of Fragile X Syndrome-the Fmr1 knockout (KO). Overall, these alterations result in hyperexcitability of neocortical circuits in the Fmr1 KO. Specifically, we observe a substantial deficit in local excitatory drive ( approximately 50%) targeting fast-spiking (FS) inhibitory neurons in layer 4 of somatosensory, barrel cortex. This persists until at least 4 wk of age suggesting it may be permanent. In contrast, monosynaptic GABAergic synaptic transmission was unaffected. Overall, these changes indicate that local feedback inhibition in neocortical layer 4 is severely impaired in the Fmr1 KO mouse. An increase in the intrinsic membrane excitability of excitatory neurons may further contribute to hyperexcitability of cortical networks. In support of this idea, persistent neocortical circuit activity, or UP states, elicited by thalamic stimulation was longer in duration in the Fmr1 KO mouse. In addition, network inhibition during the UP state was less synchronous, including a 14% decrease in synchrony in the gamma frequency range (30-80 Hz). These circuit changes may be involved in sensory stimulus hypersensitivity, epilepsy, and cognitive impairment associated with Fragile X and autism.
authors.affiliation: Dept. of Neuroscience, University of Texas, Southwestern Medical Center, Box 9111, Dallas, TX 75390-9111, USA. Jay.Gibson@UTSouthwestern.edu
authors.forename: Jay R
authors.initials: JR
authors.lastname: Gibson
authors.forename: Aundrea F
authors.initials: AF
authors.lastname: Bartley
authors.forename: Seth A
authors.initials: SA
authors.lastname: Hays
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D005246:Feedback; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000473:pathology*; D009415:Nerve Net / Q000473:pathology*; D009433:Neural Inhibition / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013788:Thalamus / Q000503:physiopathology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; C497684:Fmr1 protein, mouse
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