Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism

Soltesz, Fruzsina, Suckling, John, Lawrence, Phil, Tait, Roger, Ooi, Cinly, Bentley, Graham, Dodds, Chris M., Miller, Sam R., Wille, David R., Byrne, Misha, McHugh, Simon M., Bellgrove, Mark A., Croft, Rodney J., Lu, Bai, Bullmore, Edward T. and Nathan, Pradeep J. (2014) Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism. PLoS ONE, 9 4: e95558.1-e95558.16. doi:10.1371/journal.pone.0095558


Author Soltesz, Fruzsina
Suckling, John
Lawrence, Phil
Tait, Roger
Ooi, Cinly
Bentley, Graham
Dodds, Chris M.
Miller, Sam R.
Wille, David R.
Byrne, Misha
McHugh, Simon M.
Bellgrove, Mark A.
Croft, Rodney J.
Lu, Bai
Bullmore, Edward T.
Nathan, Pradeep J.
Title Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism
Journal name PLoS ONE   Check publisher's open access policy
ISSN 1932-6203
Publication date 2014-04-23
Sub-type Article (original research)
DOI 10.1371/journal.pone.0095558
Open Access Status DOI
Volume 9
Issue 4
Start page e95558.1
End page e95558.16
Total pages 16
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2015
Language eng
Abstract Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2015 Collection
 
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