Transcranial direct current stimulation induces hippocampal metaplasticity mediated by brain-derived neurotrophic factor

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate neuronal excitability via externally applied electric fields. Despite the positive effects of tDCS in a wide range of neurological disorders in humans, its mechanism of action remains poorly understood. Here we investigated cellular and molecular mechanisms underlying the aftereffects of anodal tDCS on the induction of long-term potentiation (LTP), a cellular correlate of learning and memory, at Schaffer collateral-CA1 synapses. We found that hippocampal CA1 LTP was enhanced in slices from rats subjected to anodal tDCS with no significant changes in basal synaptic function. The enhancing effect of tDCS on LTP was still maintained 12 h after stimulation. Treatment of ex vivo hippocampal slices from tDCS-treated rats with tropomyosin receptor kinase B (TrkB) inhibitor ANA-12, but not D1 receptor antagonist SKF-83566 or β2-adrenergic receptor antagonist propranolol, efficiently prevented tDCS-induced enhancement of LTP. The tDCS-treated rats exhibited higher levels of brain derived neurotrophic factor (BDNF) in the hippocampal CA1 region compared to sham-treated rats. Anodal tDCS also enhances memory performance in hippocampal-dependent passive avoidance learning task, and this enhancement can be blocked by ANA-12 pretreatment. Altogether, our results underscore the importance of BDNF/TrkB-mediated metaplastic effect of anodal tDCS on the induction of hippocampal CA1 LTP.