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Cited by 529Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeural dynamics and brain function

Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome

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Gibson, Jay R., Bartley, Aundrea F., Hays, Seth A., Huber, Kimberly M.·2008·Journal of Neurophysiology
DOI 10.1152/jn.90752.2008PMC PMC2585391
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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 (∼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.

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Authors
Gibson, J. R., Bartley, A. F., Hays, S. A., & Huber, K. M.
Affiliations
The University of Texas Southwestern Medical Center (US)
ORCID
Venue
Journal of Neurophysiology
Publisher
American Physiological Society
Published
2008-11
Volume
100
Issue
5
Pages
2615-2626
ISSN
  • 0022-3077 (ISSN-L)
  • 1522-1598
DOI
10.1152/jn.90752.2008
PMC
PMC2585391
OpenAlex
W1984618862
Cited by
529
References
8
Citations by year
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FWCI
12.95
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurophysiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Autism Speaks (AS2086)
  • National Institute of Neurological Disorders and Stroke (R01NS045711, NS045711)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD052731, HD-052731, R01HD056370)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
fragile X syndrome, Fmr1 knockout, excitatory-inhibitory imbalance, up states, fast-spiking interneurons, layer 4, somatosensory cortex, barrel cortex, gamma oscillations, thalamic stimulation, sensory hypersensitivity, autism spectrum disorder, epilepsy
MeSH terms
Action Potentials, Animals, Disease Models, Animal, Electric Stimulation, Feedback, Female, Fragile X Syndrome, Male, Mice, Transgenic, Nerve Net, Neural Inhibition, Synaptic Transmission, Synapses, Thalamus, Neocortex, Green Fluorescent Proteins, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, In Vitro Techniques

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