Diminished activity-dependent brain-derived neurotrophic factor expression underlies cortical neuron microcircuit hypoconnectivity resulting from exposure to mutant huntingtin fragments.
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.
Gambazzi
Luca
L
Laboratory of Neural Microcircuitry, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Gokce
Ozgun
O
Seredenina
Tamara
T
Katsyuba
Elena
E
Runne
Heike
H
Markram
Henry
H
Giugliano
Michele
M
Luthi-Carter
Ruth
R
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005822:Genetic Vectors; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008839:Microelectrodes; D015233:Models, Statistical; D009154:Mutation / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000494:pharmacology*; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D012313:RNA; D020813:Receptor, trkB