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Research ArticleNew Research, Disorders of the Nervous System

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome

D. Sinclair, R. Featherstone, M. Naschek, J. Nam, A. Du, S. Wright, K. Pance, O. Melnychenko, R. Weger, S. Akuzawa, M. Matsumoto and S. J. Siegel
eNeuro 17 February 2017, 4 (1) ENEURO.0380-16.2017; DOI: https://doi.org/10.1523/ENEURO.0380-16.2017
D. Sinclair
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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R. Featherstone
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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M. Naschek
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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J. Nam
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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A. Du
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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S. Wright
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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K. Pance
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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O. Melnychenko
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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R. Weger
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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S. Akuzawa
2Neuroscience Research Unit, DDR, Astellas Pharma Inc., Tsukuba-Shi, Ibaraki 305-8585, Japan
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M. Matsumoto
2Neuroscience Research Unit, DDR, Astellas Pharma Inc., Tsukuba-Shi, Ibaraki 305-8585, Japan
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S. J. Siegel
1Translational Neuroscience Program Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
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    Figure 1.

    Effects of baclofen on ERPs in Fmr1 KO and WT mice (F-WT, n = 16; F-KO, n = 15; M-WT, n = 23; M-KO, n = 18). A–D, Heat maps and traces showing positive and negative ERP deflections across test trials from representative WT (A, B) and Fmr1 KO (C, D) mice after vehicle and 2.5 mg/kg baclofen administration. E, Grand average waveforms with characteristic ERP deflections in all mice (female and male Fmr1 KO and WT) after vehicle or 1, 2.5, and 5 mg/kg baclofen. F, Effects of baclofen on amplitudes of the P20 component of the ERP in female and male Fmr1 KO and WT mice. G, Effects of baclofen on amplitudes of the N40 ERP component. F, female, M, male, Veh, vehicle. Error bars represent SEM.

  • Figure 2.
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    Figure 2.

    Effects of baclofen on baseline and auditory stimulus–related gamma oscillations in Fmr1 KO and WT mice (F-WT, n = 16; F-KO, n = 15; M-WT, n = 23; M-KO, n = 18). A, B, Baseline absolute power spectra in Fmr1 KO and WT mice (A), and vehicle and 5 mg/kg baclofen treatment conditions (B). C, D, Baseline relative power spectra (normalized to total 0 to 120 Hz power). E–H, Heat maps showing total power of EEG oscillations at baseline across 2 to 120 Hz frequencies from representative WT (E, F) and Fmr1 KO (G, H) mice after vehicle and 2.5 mg/kg baclofen administration. Boxes highlight baseline gamma oscillations. I, Baseline absolute gamma power. J, Baseline relative gamma power. K–N, Heat maps showing evoked power of EEG oscillations after stimulus across 2 to 120 Hz frequencies from representative WT (K, L) and Fmr1 KO (M, N) mice after vehicle and 2.5 mg/kg baclofen administration. Boxes highlight auditory-evoked gamma oscillations. O, Evoked gamma power. P, Induced gamma power. F, female, M, male, Veh, vehicle. Error bars represent SEM. *p < 0.05, ***p < 0.0005, ****p < 0.00005.

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    Figure 3.

    Effects of baclofen on behaviors in Fmr1 KO and WT mice. A, Open-field beam breaks in 10 min; F-WT, n = 18; F-KO, n = 18; M-WT, n = 22; M-KO, n = 19. B, Percentage center time spent in the open field. C, Percentage of social interactions in the three-chamber test; F-WT, n = 15; F-KO, n = 15; M-WT, n = 18; M-KO, n = 19. D, Percentage of correct spontaneous alternations in the continuous T-maze task; F-WT, n = 17; F-KO, n = 18; M-WT, n = 22; M-KO, n = 19. E, Average latency to find the platform during test trials in the modified radial water maze; F-WT, n = 18; F-KO, n = 18; M-WT, n = 18; M-KO, n = 18. F, female, M, male, Veh, vehicle. Error bars represent SEM. *p < 0.05, ***p < 0.0005.

  • Figure 4.
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    Figure 4.

    Relationships between changes in gamma power and improvements in T-maze performance after 2.5 mg/kg baclofen. A–C, Differences in T-maze performance between baseline relative gamma responders and baseline relative gamma nonresponders. D, E, Correlation of changes in relative baseline gamma power after 2.5 mg/kg baclofen with changes in T-maze performance in WT and Fmr1 KO mice. F–H, Differences in T-maze performance between evoked gamma responders and evoked gamma nonresponders. I, J, Correlation of changes in evoked gamma power after 2.5 mg/kg baclofen with changes in T-maze performance in WT mice and Fmr1 KO mice. BAC, baclofen, N.S., not significant. Error bars represent SEM. **p ≤ 0.005.

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GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome
D. Sinclair, R. Featherstone, M. Naschek, J. Nam, A. Du, S. Wright, K. Pance, O. Melnychenko, R. Weger, S. Akuzawa, M. Matsumoto, S. J. Siegel
eNeuro 17 February 2017, 4 (1) ENEURO.0380-16.2017; DOI: 10.1523/ENEURO.0380-16.2017

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GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome
D. Sinclair, R. Featherstone, M. Naschek, J. Nam, A. Du, S. Wright, K. Pance, O. Melnychenko, R. Weger, S. Akuzawa, M. Matsumoto, S. J. Siegel
eNeuro 17 February 2017, 4 (1) ENEURO.0380-16.2017; DOI: 10.1523/ENEURO.0380-16.2017
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Keywords

  • EEG
  • fragile X syndrome
  • GABA
  • gamma
  • Racemic Baclofen
  • working memory

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