Repetitive transcranial magnetic stimulation enhances spatial learning and synaptic plasticity via the VEGF and BDNF-NMDAR pathways in a rat model of vascular dementia

Neuroscience. 2015 Dec 17;311:284-91. doi: 10.1016/j.neuroscience.2015.10.038. Epub 2015 Oct 27.


This study aimed to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on learning and memory in a rat model of vascular dementia (VaD) and to analyze the associated mechanisms. Bilateral carotid artery occlusion (2-VO) was used to establish a rat model of VaD. High-frequency (5Hz) rTMS was performed on rats for four weeks. Spatial learning and memory abilities were evaluated using the Morris water maze (MWM), and synaptic plasticity in the hippocampus was assessed via long-term potentiation (LTP). Hippocampal expression of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) and three subunits of the N-methyl-D-aspartic acid receptor (NMDAR), NR1, NR2A and NR2B, was analyzed by Western blotting. Compared with the VaD group, escape latency was decreased (P<0.05) and the time spent in the target quadrant and the percentage of swimming distance within that quadrant were increased (P<0.05) in the rTMS group. LTP at hippocampal CA3-CA1 synapses was enhanced by rTMS (P<0.05). VEGF expression was up-regulated following 2-VO and was further increased by rTMS (P<0.05). BDNF, NR1 and NR2B expression was decreased in the VaD group and increased by rTMS (P<0.05). There were no significant differences in NR2A expression among the three groups. These results suggest that rTMS improved learning and memory in the VaD model rats via the up-regulation of VEGF, BDNF and NMDARs. In addition, NR2B may be more important than NR2A for LTP induction in the hippocampus during rTMS treatment of VaD.

Keywords: BDNF; N-methyl-d-aspartic acid receptor; VEGF; long-term potentiation; repetitive transcranial magnetic stimulation; vascular dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dementia, Vascular / physiopathology*
  • Dementia, Vascular / psychology
  • Dementia, Vascular / therapy*
  • Disease Models, Animal
  • Hippocampus / physiopathology
  • Long-Term Potentiation / physiology*
  • Male
  • Maze Learning / physiology
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Signal Transduction / physiology
  • Spatial Learning / physiology*
  • Transcranial Magnetic Stimulation / methods*
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / metabolism


  • Brain-Derived Neurotrophic Factor
  • NR1 NMDA receptor
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • N-methyl D-aspartate receptor subtype 2A