P020 Epigenetic regulation of brain-derived neurotrophic factor (Bdnf) expression mediates the effects of anodal transcranial direct current stimulation (tDCS) on hippocampal synaptic plasticity and memory in mice

Abstracts / Clinical Neurophysiology 128 (2017) e1–e163

doi:10.1016/j.clinph.2016.10.148

P020 Epigenetic regulation of brain-derived neurotrophic factor (Bdnf) expression mediates the effects of anodal transcranial direct current stimulation (tDCS) on hippocampal synaptic plasticity and memory in mice—M.V. Podda a, S. Cocco a, A. Mastrodonato a, S. Fusco a, L. Leone a, S.A. Barbati a, C. Colussi b, G. Livrizzi a, C. Ripoli a, C. Grassi a,* (a Università Cattolica, Institute of Human Physiology, Rome, Italy, b CNR, IBCN, Rome, Italy) ⇑

Corresponding author.

Question: Understanding the cellular and molecular mechanisms underlying tDCS action is critical for a rationale use of this technique

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in clinical settings. Here we investigated the effects of tDCS on hippocampal synaptic plasticity and memory focusing on epigenetic mechanisms affecting the expression of plasticity-related genes. Methods: Electrophysiological, behavioral and molecular indices of hippocampal plasticity were investigated following 20-min anodal tDCS delivered to awake mice. Results: Hippocampal slices from tDCS-mice showed greater longterm potentiation (LTP) at CA3-CA1 synapses compared to shamstimulated controls. Enhanced LTP was associated with improved hippocampal-dependent learning and memory assessed by the Morris water maze and novel object recognition tests. Remarkably, all these effects persisted 1 week after tDCS. Real-time PCR, Western Blotting and chromatin immunoprecipitation experiments revealed that tDCS effects were due to an intracellular signaling cascade including: (i) increased phosphorylation of cAMP response element-binding protein (CREB); (ii) enhanced CREB binding to the Bdnf promoter I; and, (iii) recruitment of the histone acetyltransferase CBP (CREB-binding protein) leading to enhanced histone 3

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Abstracts / Clinical Neurophysiology 128 (2017) e1–e163

acetylation on Bdnf promoter I. As a consequence, the expression of Bdnf exons I and IX mRNAs was increased in the hippocampi of tDCS mice along with Bdnf protein levels. Accordingly, molecular, electrophysiological and behavioral effects of tDCS were prevented by mice treatment with either the acetylation inhibitor, curcumin, or the Bdnf receptor TrkB antagonist, ANA-12. Remarkably, we found that tDCS enhanced glycogen synthase kinase-3b(GSK-3b) phosphorylation at Ser9 that was prevented by ANA-12, thus suggesting that GSK-3binhibition plays a role in the tDCS-induced increase of hippocampal plasticity. Conclusion: Our findings show that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene. These results lend support to the use of tDCS for prevention and treatment of brain diseases associated with impaired neuroplasticity.

Figure 1: Correlation between silent period and axial subset scores. SMA, supplementary motor area; PMd, dorsal premotor area.

doi:10.1016/j.clinph.2016.10.149

P021 Differential clinical and neurophysiological outcomes after premotor rTMS in Parkinson’s disease—M. Biagioni *, A. Son, S. Agarwal, R. Gilbert, A. Quartarone, A. DiRocco (Fresco Institute at NYU Langone Medical Center, Neurology, New York City, United States) ⇑

Corresponding author.

Question: Weekly sessions of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over supplementary motor area (SMA) have shown motor improvement as add-on therapy for Parkinson’s disease (PD). We conducted an active-controlled study to explore potential additive effects of rTMS over both SMA and dorsal premotor area (PMd) compared to SMA alone and potential neurophysiological (NPh) correlates. Methods: PD patients with Hoehn & Yahr scores 2–3 participated in a parallel double-blind randomized study of four weekly sessions of LF rTMS. Intervention arms were rTMS over SMA (SMA-alone) and rTMS over both PMd and SMA (PMd + SMA). Clinical outcomes were Unified Parkinson’s Disease Rating Scale-III (UPDRS-III) score; axial, tremor, rigidity, and bradykinesia sub-scores. NPh outcomes were motor evoked potentials, cortical silent period (SP), short interval intra-cortical inhibition and intra-cortical facilitation. Outcomes were analyzed at baseline and 4-weeks post-treatment completion.

Results: Baseline demographics in Table 1; 14 patients completed all study visits. UPDRS-III improved in both arms, SMA-alone (19.8%, p < 0.05) and PMd + SMA (21.0%, p < 0.05). SMA-alone significantly decreased bradykinesia sub-scores (BrS) (z = -2.21, p < 0.05) while PMd + SMA decreased both BrS (z = -2.0, p < 0.05) and axial subscores (AxS) (z = -2.4, p < 0.05). NPh outcomes revealed significant increase of SP in PMd + SMA vs. SMA-alone (U = 7.0, p < 0.05). Also, the change in SP showed mod-high correlation with the change in AxS when participants were pooled together (r = -0.60, p < 0.05; Fig. 1). Other NPh outcomes were not significant. Conclusions: We confirmed weekly LF premotor rTMS can improve motor scores and BrS. AxS improvement seen in the PMd + SMA arm

Table 1: Baseline demographics. SMA, supplementary motor area; PMd, dorsal premotor area; UPDRS, Unified Parkinson’s Disease Rating Scale.