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Research ArticleNEUROPHARMACOLOGY

Diminished Activity-Dependent Brain-Derived Neurotrophic Factor Expression Underlies Cortical Neuron Microcircuit Hypoconnectivity Resulting from Exposure to Mutant Huntingtin Fragments

Luca Gambazzi, Ozgun Gokce, Tamara Seredenina, Elena Katsyuba, Heike Runne, Henry Markram, Michele Giugliano and Ruth Luthi-Carter
Journal of Pharmacology and Experimental Therapeutics October 2010, 335 (1) 13-22; DOI: https://doi.org/10.1124/jpet.110.167551
Luca Gambazzi
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Ozgun Gokce
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Tamara Seredenina
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Elena Katsyuba
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Heike Runne
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Henry Markram
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Michele Giugliano
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Ruth Luthi-Carter
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Abstract

Although previous studies of Huntington's disease (HD) have addressed many potential mechanisms of striatal neuron dysfunction and death, it is also known, based on clinical findings, that cortical function is dramatically disrupted in HD. With respect to disease etiology, however, the specific molecular and neuronal circuit bases for the cortical effects of mutant huntingtin (htt) have remained largely unknown. In the present work, we studied the relationship between the molecular effects of mutant htt fragments in cortical cells and the corresponding behavior of cortical neuron microcircuits by using a novel cellular model of HD. We observed that a transcript-selective diminution in activity-dependent brain-derived neurotrophic factor (BDNF) expression preceded the onset of a synaptic connectivity deficit in ex vivo cortical networks, which manifested as decreased spontaneous collective burst-firing behavior measured by multielectrode array substrates. Decreased BDNF expression was determined to be a significant contributor to network-level dysfunction, as shown by the ability of exogenous BDNF to ameliorate cortical microcircuit burst firing. The molecular determinants of the dysregulation of activity-dependent BDNF expression by mutant htt seem to be distinct from previously elucidated mechanisms, because they do not involve known neuron-restrictive silencer factor/RE1-silencing transcription factor-regulated promoter sequences but instead result from dysregulation of BDNF exon IV and VI transcription. These data elucidate a novel HD-related deficit in BDNF gene regulation as a plausible mechanism of cortical neuron hypoconnectivity and cortical function deficits in HD. Moreover, the novel model paradigm established here is well suited to further mechanistic and drug screening research applications.

Footnotes

  • This work was supported by the European Sixth Framework Program NeuroNano [Grant NMP4-CT-2006-031847], the European Sixth Framework Program Early-Stage Researchers Training Program in Nervous System Repair, the Telethon Action Suisse, a Commission for Technology and Innovation award from the Swiss National Science Foundation, the Ecole Polytechnique Fédérale de Lausanne, the University of Antwerp (Nieuwe Onderzoeks Initiatieven Bijzonder Onderzoeksfonds), and the Belgian Interuniversity Attraction Pole.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.167551.

  • ABBREVIATIONS:

    HD
    Huntington's disease
    htt
    huntingtin
    BDNF
    brain-derived neurotrophic factor
    PB
    population burst
    IBI
    interburst interval
    MEA
    multielectrode array
    STH
    spike-time histogram
    PBS
    phosphate-buffered saline
    NRSF
    neuron-restrictive silencer factor
    REST
    RE1-silencing transcription factor
    DIV
    days in vitro
    tTA1
    tetracycline-regulatable transactivator
    H-89
    N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide·2HCl
    PCR
    polymerase chain reaction
    P
    postnatal day.

  • Received February 22, 2010.
  • Accepted July 12, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleNEUROPHARMACOLOGY

Diminished Activity-Dependent Brain-Derived Neurotrophic Factor Expression Underlies Cortical Neuron Microcircuit Hypoconnectivity Resulting from Exposure to Mutant Huntingtin Fragments

Luca Gambazzi, Ozgun Gokce, Tamara Seredenina, Elena Katsyuba, Heike Runne, Henry Markram, Michele Giugliano and Ruth Luthi-Carter
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 13-22; DOI: https://doi.org/10.1124/jpet.110.167551

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Research ArticleNEUROPHARMACOLOGY

Diminished Activity-Dependent Brain-Derived Neurotrophic Factor Expression Underlies Cortical Neuron Microcircuit Hypoconnectivity Resulting from Exposure to Mutant Huntingtin Fragments

Luca Gambazzi, Ozgun Gokce, Tamara Seredenina, Elena Katsyuba, Heike Runne, Henry Markram, Michele Giugliano and Ruth Luthi-Carter
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 13-22; DOI: https://doi.org/10.1124/jpet.110.167551
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