Linked Life Data

20624994

Source:http://linkedlifedata.com/resource/pubmed/id/20624994

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2010-9-21
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
335
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
13-22
pubmed:meshHeading
pubmed-meshheading:20624994-Animals, pubmed-meshheading:20624994-Brain-Derived Neurotrophic Factor, pubmed-meshheading:20624994-Cerebral Cortex, pubmed-meshheading:20624994-Genetic Vectors, pubmed-meshheading:20624994-Huntington Disease, pubmed-meshheading:20624994-Immunohistochemistry, pubmed-meshheading:20624994-Lentivirus, pubmed-meshheading:20624994-Microelectrodes, pubmed-meshheading:20624994-Models, Statistical, pubmed-meshheading:20624994-Mutation, pubmed-meshheading:20624994-Nerve Net, pubmed-meshheading:20624994-Nerve Tissue Proteins, pubmed-meshheading:20624994-Neural Pathways, pubmed-meshheading:20624994-Neurons, pubmed-meshheading:20624994-Nuclear Proteins, pubmed-meshheading:20624994-Peptide Fragments, pubmed-meshheading:20624994-RNA, pubmed-meshheading:20624994-Rats, pubmed-meshheading:20624994-Rats, Wistar, pubmed-meshheading:20624994-Receptor, trkB, pubmed-meshheading:20624994-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:20624994-Synapses
pubmed:year
2010
pubmed:articleTitle
Diminished activity-dependent brain-derived neurotrophic factor expression underlies cortical neuron microcircuit hypoconnectivity resulting from exposure to mutant huntingtin fragments.
pubmed:affiliation
Laboratory of Neural Microcircuitry, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't