Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex
Introduction
The inter-individual variability of human neuroplasticity is an area of increasing interest (Fried et al., 2017, López-Alonso et al., 2014, Ridding and Ziemann, 2010). Neuroplasticity subserves many functions including learning and memory, and may impact the success of compensatory measures in neurological disorders and response to therapy (Pearson-Fuhrhop et al., 2012). Brain-derived neurotrophic factor (BDNF) is understood to help orchestrate synaptic plasticity and the most widely expressed neurotrophin in the mammalian brain (Park and Poo, 2013).
In-vitro and in-vivo research indicates that the influence of BDNF extends beyond neuroplasticity to more fundamental properties of synaptic transmission, and that such properties could underpin some of the effects of BDNF on neuroplasticity (Figurov et al., 1996, Gottschalk et al., 1998). More specifically, cell-slice studies indicate that BDNF has a wide array of effects on synaptic transmission at excitatory and inhibitory synapses, enhancing neurotransmitter release (Pattwell et al., 2012), increasing synaptic density (Marty et al., 2000), and promoting synaptic maturation (Bulleit and Hsieh, 2000). Interestingly, application of exogenous BDNF to BDNF knockout mice ameliorates deficits in both synaptic transmission and plasticity (Patterson et al., 1996, Pattwell et al., 2012). Moreover, BDNF antibodies only affect plasticity induction when applied prior to or during stimulation, but have no effect when applied following stimulation, suggesting that the effects of BDNF on neurotransmission may mediate its effects on neuroplasticity (Chen et al., 1999).
In addition, emerging evidence suggests that BDNF plays a role in setting the balance between excitatory and inhibitory postsynaptic transmission, quantified as the excitatory to inhibitory (E/I) ratio (Singh et al., 2006). Rather than considering excitatory and inhibitory circuits in isolation, the E/I balance describes whether the strength of these circuits is balanced or potentially dysregulated. In vitro and in vivo animal research indicates that the E/I balance is crucial for maintaining postsynaptic neural firing activity within the dynamic range (Eichler and Meier, 2008, Rutherford et al., 1997, Shu et al., 2003), and for the fine tuning of oscillatory neural dynamics as well as neural computation required for higher order cognitive and network function (Denève and Machens, 2016, Gandal et al., 2012, Haider et al., 2006, Liu, 2004, Yizhar et al., 2011). This balance has been proposed as a functional cornerstone of neural circuitry (Dehghani et al., 2016), due its role in maintaining normal dynamic function within neural circuits (Deneve and Machens, 2016, Eichler and Meier, 2008, Haider et al., 2006, Rutherford et al., 1997, Shu et al., 2003, Gandal et al., 2012), while dysregulation of this balance has been noted as a common feature among neuropsychiatric disorders (Bartley and Dobrunz, 2015, Uhlhaas and Singer, 2012, Yizhar et al., 2011). These findings provide motivation to explore the relation between BDNF, neurocircuitry and plasticity in human cortex.
The influence of BDNF can be studied in human via the common single nucleotide polymorphism (SNP) at nucleotide 196 (G/A), which is associated with decreased activity dependent secretion of BDNF due to a valine-to-methione substitution at codon 66 (Val66Met) (Egan et al., 2003). Transcranial magnetic stimulation (TMS) provides a non-invasive method for the investigation of neurocircuitry and plasticity, and their relation, in human cortex. TMS measures probing excitatory and inhibitory neurocircuitry include, amongst others, short interval intracortical facilitation (SICF) and short and long interval intracortical inhibition (SICI, LICI), which are considered to index the strength of gamma-aminobutyric acid type A (GABAA) and B (GABAB) receptor mediated inhibition respectively (for review see Cash and Ziemann, 2021, Paulus et al., 2008). Neuroplasticity may be studied via a variety of TMS protocols, and while the systems-level effects of TMS may not be identical to those examined in classical single cell paradigms, there are common features (Thickbroom, 2007, Ziemann et al., 2008). Accordingly, the persistent increases (long term potentiation, LTP) and decreases (long term depression, LTD) in excitability observed in cell-slice studies are referred to as LTP- and LTD-like when studied using TMS. Interestingly, both rodent and human studies indicate that the extent to which BDNF influences plasticity varies across different stimulation paradigms. For example, cell slice studies indicate that higher BDNF levels promote the plastic effects of theta burst stimulation (TBS), but not continuous high frequency stimulation (Akaneya et al., 1997, Chen et al., 1999, Figurov et al., 1996, Kang et al., 1997). In human motor cortex, the plastic effects of TBS appear to be reliably modulated by BDNF genotype (Antal et al., 2010, Cheeran et al., 2008), whereas the relationship appears to be weaker or even absent for transcranial direct current stimulation (Antal et al., 2010, Di Lazzaro et al., 2012, Loo et al., 2018), conventional repetitive TMS (Hwang et al., 2015) and quadri-pulse stimulation (Nakamura et al., 2011).
In the present work, we examined a plasticity paradigm termed I-wave TMS (ITMS). ITMS plasticity is understood to be mediated by SICF excitatory circuitry (Cash et al., 2009, Cash et al., 2013, Cash et al., 2016, Thickbroom et al., 2006). This link provides a unique and attractive opportunity to investigate the relationship between BDNF effects on neural circuit properties and cortical plasticity. In short, ITMS involves repeated delivery of paired pulse stimuli, and LTP- or LTD-like effects are induced depending on whether stimuli are repeatedly timed to coincide with SICF phases of increased (1.5 ms interstimulus interval, ISI) or decreased neural excitability (2 ms ISI) (Cash et al., 2013). By individualising these intervals to match the timing of the subject-specific SICF peak (∼1.5 ms) or trough (∼2ms), ITMS LTP- and LTD-like effects can be further enhanced (Cash et al., 2016, Sewerin et al., 2011). On this basis, ITMS is understood to be mediated by a process termed phase dependent plasticity, in which plastic effects depend on whether stimulation is delivered during moments of increased or decreased neural excitability (Cash et al., 2013).
In the present study we investigated whether the influence of BDNF extends beyond neuroplasticity to more fundamental neural circuit properties. More specifically, we assessed in motor cortex (i) the impact of BDNF Val66Met genotype on paired-pulse measures of excitatory and inhibitory signalling (SICF, SICI, LICI), (ii) introduce a TMS measure of the E/I balance, based on indexes of excitatory and inhibitory transmission (i.e. SICF, SICI) which operate on a similar (rapid) time-scale, and examine the influence of BDNF genotype on this balance and (iii) assessed the impact of BDNF genotype on excitatory and depressive forms of ITMS plasticity and (iv) investigated whether a higher threshold for plasticity induction in Met allele carriers could be related to reduced excitatory neurotransmission and therefore negated by compensatory increases in TMS intensity.
Section snippets
Participants
We studied 18 healthy volunteers: 9 Val homozygotes (4 female; aged 35 ± 2 years) and 9 Met allele carriers (5 female; aged 33 ± 4 years), two of whom were Met/Met homozygotes. All participants provided written informed consent in accordance with the Declaration of Helsinki and the protocol had the approval of the University Health Network (Toronto) Research Ethics Board.
BDNF genotyping/ genetic analysis
Each participant donated 30 mL of whole blood. DNA was extracted using the high-salt technique previously described (Lahiri
RMT and SI1mV
There were no significant differences between Val/Val and Met groups in RMT (49 ± 4 and 49 ± 4% MSO respectively; P = 0.89) or the intensity required to generate 1 mV peak-to-peak MEP amplitude (62 ± 5 and 68 ± 5% MSO respectively; P = 0.44; Table 1).
LICI
There was a significant effect of CS intensity (F(2,17.4) = 30.0, P < 0.01, d = 1.23, β = 0.69), group (F(1,23.8) = 7.3, P < 0.05 d = 1.10, β = 0.59) and their interaction on LICI (F(2,17.4) = 3.8, P < 0.05, d = 0.44, β = 0.14). This reflects the
Discussion
These findings provide initial evidence that the influence of BDNF in human extends beyond neuroplasticity to more fundamental aspects of synaptic transmission. Our data indicate a relation between BDNF genotype and the strength of excitatory and inhibitory neural circuitry, as indexed using TMS. To demonstrate circuit specificity, we utilised ISI curves for SICF and intensity curves for LICI. Our data across 18 participants further indicate that a balance between the strength of excitatory and
Limitations
A limitation with the present work is the relatively small sample size. While this appeared comparable to and justified based on prior work (section 2.1.3), the findings should be considered as preliminary and require replication in larger samples. A range of parameters can be employed to measure SICI and SICF and these often vary across studies. We carefully selected paired-pulse parameters to avoid floor or ceiling effects, as these would otherwise reduce capacity to detect between-group
Conclusions
These findings provide initial evidence that the influence of BDNF in human extends beyond neuroplasticity to more fundamental aspects of synaptic transmission. Furthermore, the results provide novel evidence that it may be possible to compensate for reductions in TMS plasticity by individually adjusting for reduced excitatory transmission. Our data indicate that a balance between the strength of excitatory and inhibitory circuits (E/I ratio) may be an intrinsic feature of human motor cortex
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We thank all participants. We thank Dr Anurika De Silva at the University of Melbourne for helpful discussions.
Funding
RFHC received support from the Canadian Institutes of Health Research (grant number DFF211888) and Australian Research Council (DE200101708). KU was supported by Canadian Institutes of Health Research (grant number 201010DFF-236001-172378). This work was also supported by Canadian Institutes of Health Research (grant number FDN 154292). In the last 3 years, ZJD received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. ZJD has
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