Diminished activity-dependent brain-derived neurotrophic factor expression underlies cortical neuron microcircuit hypoconnectivity resulting from exposure to mutant huntingtin fragments

The Journal of Pharmacology and Experimental Therapeutics
Luca GambazziRuth Luthi-Carter

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 expressi...Continue Reading

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Citations

Feb 9, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·David M TaylorRuth Luthi-Carter
Jul 6, 2014·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Ravi Chopra, Vikram G Shakkottai
Jan 10, 2012·Neurobiology of Disease·Shilpa Ramaswamy, Jeffrey H Kordower
Sep 17, 2015·Journal of Theoretical Biology·Jakub RydzewskiGiuseppe Nicosia
Aug 9, 2011·Neurobiology of Disease·Tamara Seredenina, Ruth Luthi-Carter
Jan 18, 2013·Prion·Marta GiacomelloErnesto Carafoli
Aug 10, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sorabh Sharma, Rajeev Taliyan
Aug 16, 2016·Scientific Reports·Yanchun PanHiroko Yano
Apr 9, 2019·Cerebral Cortex·Anastasiya MoskalyukMichele Giugliano
Jun 13, 2018·Nature Nanotechnology·Niccolò Paolo PampaloniDenis Scaini

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