IS 37. Repetitive transcranial magnetic stimulation enhances BDNF–TrkB signaling in both brain and lymphocyte

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain-stimulation procedure noted for its effects on emotional, cognitive, sensory, and motor functions in patients with neuropsychiatric diseases. Despite the large use of rTMS in different neuroscience fields the precise mechanism of this technique remain poorly understood. It is likely that rTMS induces long-term potentiation (LTP) or depression, which, in turn, produce lasting changes on neocortical excitability and synaptic connections. In recent years, brain-derived neurotrophic factor (BDNF) and its cognate receptor tyrosine receptor kinase B (TrkB), a member of the neurotrophin receptor tyrosine kinase family, have emerged as important upstream regulators of LTP in brain regions, including hippocampus and neocortex (Minichiello, 2009; Fritsch et al., 2010). In keeping with these findings we have recently reported that daily 5 Hz rTMS for 5 d improves BDNF–TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC- γ 1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF–TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF-TrkB signaling and intensified TrkB–NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF–TrkB–NMDAR functioning in both cortex and lymphocytes. We propose TMS as a non invasive tool to test the NMDA receptor machinery at a molecular level.