Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning

Abstract

Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNF-secretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

Fig. 1. DCS promotes LTP in motor cortical slices

A, Schematic diagram of DCS and recording from motor cortex (M1) slices. The distribution of the electrical field strength (0.75 mV/mm in the motor cortex) is superimposed onto M1 of a coronal slice. B, Group data showing the fEPSP amplitude before, during 15 minutes of DCS, and up to 30 minutes after DCS. C, Summary graph and sample fEPSPs showing a 2 hr time course after DCS. The grey vertical line indicates the end of recording in all other slice recordings. D, Application of D-AP V (50μM) abolishes the DCS-LTP. E, The amplitude and the typical change in morphology of fEPSPs of slices treated with a touch application of the GABA_A-antagonist bicuculline (BIC, 3.5 mM, sample traces) is shown.

Fig. 2. Role of BDNF and TrkB in DCS-LTP

A, Lack of DCS–LTP in M1 slices from conditional BDNF knock-out mice and littermate wild-type mice. B, Blockade of DCS-LTP by TrkB-IgG. M1 slices were treated with TrkB-IgG + BSA or BSA only. C, DCS-LTP in slices from TrkB^F616A mice. TrkB^F616A slices exhibit normal DCS-LTP (grey filled diamonds). Continuous treatment with 1NMPP1 (5 μM) completely prevents DCS-LTP (black filled diamonds). 1NMPP1 (5 μM) applied after DCS partially reduces DCS-LTP (open diamonds). D, Anodal DCS in combination with repeated synaptic coactivation (+ LFS +DCS, right dark grey bar) significantly increased TrkB phosphorylation relative to LFS alone (+LFS −DCS, left light grey bar). M1 lysates from slices which underwent either LFS alone or in combination with 15 min DCS were subjected to SDS-PAGE and Western blotted for p-TrkB and total TrkB, The level of p-TrkB was normalized to total TrkB..*** p<0.001.

Fig. 3. Effect of BDNF Val66Met polymorphism on motor skill acquisition in human and mice

A, Motor skill measure in humans plotted over 5 training days (6 blocks/day). Subjects carrying a Met allele show reduced skill acquisition compared to Val/Val subjects. B, Skill measures of individuals at the beginning (d 1) and the end (d 5) of the training. C, Total improvement in motor skill (ΔSkill measure end of d5 - beginning of d1) was greater inVal/Val subjects than in Met carriers in both “Sham” and “Anodal” tDCS groups. Anodal tDCS over M1 during training increased skill improvement in both groups. D, The BDNF^Met/Met mice (black circles) show reduced running skill on the accelerating rotarod at the end of the 5 day training course (6 trials/day) compared to wild type mice (white squares). E, Performance of individual mice on the rotarod at the beginning (d 1) and the end (d 5) of the training F, Skill improvement (Δtime on rod, end of d5 -beginning of d1) in wild type and the BDNF^Met/Met mice. Wild type mice improved significantly more than the BDNF^Met/Met mice. G, Effect of a forebrain specific BDNF knockout on motor skill acquisition in mice. The BDNF ^+Cre/flox mice (black circles) show reduced running skill on the accelerating rotarod at the end of the 5 day training course (6 trials/day) compared to cre negative wild type mice (white squares). H, Performance of individual BDNF mutant mice at the beginning (d 1) and end (d 5) of the training. I, Skill improvement (Δtime on rod, end of d5 -beginning of d1) in wild type and the BDNF ^+Cre/flox mice. Wild type mice improved significantly more than the BDNF ^+Cre/flox mice. All data (except single subjects in B, E, H) indicate group means, error bars represent S.E.M. *p<0.05, ** p<0.01.