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Circuit level defects in the developing neocortex of Fragile X mice

Nature Neuroscience volume 16, pages 903–909 (2013)Cite this article

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Abstract

Subtle alterations in how cortical network dynamics are modulated by different behavioral states could disrupt normal brain function and underlie symptoms of neuropsychiatric disorders, including Fragile X syndrome (FXS). Using two-photon calcium imaging and electrophysiology, we recorded spontaneous neuronal ensemble activity in mouse somatosensory cortex. Unanesthetized Fmr1−/− mice exhibited abnormally high synchrony of neocortical network activity, especially during the first two postnatal weeks. Neuronal firing rates were threefold higher in Fmr1−/− mice than in wild-type mice during whole-cell recordings manifesting Up/Down states (slow-wave sleep, quiet wakefulness), probably as a result of a higher firing probability during Up states. Combined electroencephalography and calcium imaging experiments confirmed that neurons in mutant mice had abnormally high firing and synchrony during sleep. We conclude that cortical networks in FXS are hyperexcitable in a brain state–dependent manner during a critical period for experience-dependent plasticity. These state-dependent network defects could explain the intellectual, sleep and sensory integration dysfunctions associated with FXS.

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Figure 1: Delayed network desynchronization in the neocortex of unanesthetized Fmr1−/− mice.
Figure 2: A higher proportion of L2/3 neurons are recruited to peaks of synchrony in unanesthetized Fmr1−/− mice.
Figure 3: Elevated firing rates in unanesthetized Fmr1−/− mice during Up/Down states.
Figure 4: Higher probability of neuronal firing during Up states in Fmr1−/− mice.
Figure 5: Fmr1−/− mice exhibit abnormal modulation of neuronal activity in different brain states.
Figure 6: The synchrony of L2/3 cortical pyramidal neurons is not modulated by anesthesia in Fmr1−/− mice.

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Acknowledgements

We thank D. Buonomano, C. Houser, I. Mody and R. Mostany, as well as D. Cantu for helpful discussions and/or valuable comments on the manuscript. We also thank A. Bragin and M. Blumberg for help with EEG recordings and interpretation, J. Gornbein and D. Markovich for help with statistical analyses, and W. Greenough for providing the Fmr1−/− mice. This work was supported by grants from the National Institute of Child Health and Human Development (R01HD054453), the National Institute of Neurological Disorders and Stroke (RC1NS068093), the FRAXA Research Foundation and the Dana Foundation.

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  1. J Tiago Gonçalves & James E Anstey

    Present address: Present address: The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California, USA (J.T.G.), and Oregon Health and Science University School of Medicine, Portland, Oregon, USA (J.E.A.).,

Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA

    J Tiago Gonçalves, James E Anstey, Peyman Golshani & Carlos Portera-Cailliau

  2. Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA

    Carlos Portera-Cailliau

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  1. J Tiago Gonçalves
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Contributions

J.T.G. and C.P.-C. conceived the project and designed the experiments. J.T.G., J.E.A. and P.G. conducted the experiments and analyzed the data. J.T.G. and C.P.-C. prepared the figures and wrote the manuscript. C.P.-C. supervised the project.

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Correspondence to Carlos Portera-Cailliau.

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Gonçalves, J., Anstey, J., Golshani, P. et al. Circuit level defects in the developing neocortex of Fragile X mice. Nat Neurosci 16, 903–909 (2013). https://doi.org/10.1038/nn.3415

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