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.

Fruzsina Soltész,Phil Lawrence,Sam R Miller,Bai Lu,Graham Bentley,Chris M Dodds,Roger Tait,John Suckling,David R Wille,Edward T Bullmore,Mark A Bellgrove,Misha Byrne,Rodney J Croft,Cinly Ooi,Simon M Mchugh,Pradeep J Nathan,Michael A Fox

doi:10.1371/journal.pone.0095558

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.

Highlights

The brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor type B (TrkB) are widely distributed in the human brain and play a significant role in supporting neuronal structure and function
As part of a larger investigation into the role of BDNF on synaptic and neural network activity in humans, we focused our investigation on electrophysiological markers including error-related negativity (ERN), Mismatch Negativity (MMN), resting EEG activity/synchronization and P300
Correct and error Reaction times (RT) were entered into a two-way mixed design analysis of variance (ANOVA) with Response Type (Correct vs. Error) as within-subject and Group as between-subject factor

Summary

Introduction

The brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor type B (TrkB) are widely distributed in the human brain and play a significant role in supporting neuronal structure and function. In vitro experiments have shown that BDNF enhances synaptic transmission via multiple mechanisms. BDNF is widely distributed in the human brain, its expression is reduced in neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease and Parkinson disease [9,10,11,12,13,14]. The possible role of BDNF in mood and psychiatric disorders, such as bipolar disorder and clinical depression, has been indicated by several studies (for reviews see [15,16,17]). Therapeutic strategies aimed at synaptic repair and regeneration may be a viable strategy as disease-modifying treatment of neurodegenerative diseases (see review by [18]; [14,16,19])

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