High frequency repeated transcranial magnetic stimulation improves learning and memory of global cerebral ischemia rats and its mechanism

Objective To study the effect of high frequency repeated transcranial magnetic stimulation (rTMS) on learning and memory in rats with global cerebral ischemia and to investigate its mechanism. Methods Thirty-five male Sprague-Dawley rats (8-10 weeks old) were randomly divided into sham operation group (n=8), model group (n=9), sham-rTMS (s-rTMS) group (n=9) and rTMS group (n=9). The global cerebral ischemia model was established by modified four-vessel occlusion method. The rTMS group received 10 Hz rTMS stimulation for two weeks, whereas the s-rTMS group received sham stimulation. Morris water maze test was used to detect the spatial learning ability, multi-channel recording technique was used to detect the local field potentials in the hippocampus CA1 region of theta and gamma oscillation, and immunohistochemical staining and Western blotting were used to detect the expression of protein kinase A (PKA) and phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) of hippocampus. Results The average escape latency in the model group was longer than that in the sham operation group ((35.16±0.80) s vs (16.57±0.74) s, k=3.723, P=0.013), the spanning platform times and the original platform quadrant swimming time in the model group were shorter than that in the sham operation group (1.14±0.42 vs 4.46±0.23, k=3.185, P=0.042; (14.46±0.73) s vs (29.31±0.42) s, k=3.027, P=0.047). Compared with the sham operation group, the mean power spectral density of theta and gamma reduced ((-68.48±2.61) Hz vs (-59.38±2.25) Hz, k=2.958, P=0.048; (-82.23±4.60) Hz vs (-70.50±4.25) Hz, k=3.729, P=0.021), and the expression of PKA and p-CREB protein decreased in the model group (7 184.26±975.12 vs 25 137.35±1 010.62, k=3.588, P=0.027; 1 803.73±336.18 vs 20 175.25±727.23, k=2.912, P=0.049). The average escape latency in the rTMS group was shorter than that in the model group ((24.69±1.01) s vs (35.16±0.80) s, k=4.082, P=0.034), and the spanning platform times and the original platform quadrant swimming time in the rTMS group was longer than that in the model group (2.42±0.31 vs 1.14±0.42, k=3.296, P=0.039; (23.07±0.67) s vs (14.46±0.73) s, k=4.323, P=0.012). Compared with the rTMS group, the power spectral density of theta and gamma reduced ((-63.81±3.12) Hz vs (-68.48±2.61) Hz, k=3.582, P=0.015; (-75.80±4.58) Hz vs (-82.23±4.60) Hz, k=4.051, P=0.026), and the expression of PKA and p-CREB protein decreased in the model group (13 065.32±1 045.18 vs 7 184.26±975.12, k=3.923, P=0.031;11 032.83±562.86 vs 18 03.73±336.18, k=3.178, P=0.038). Conclusion High frequency rTMS could improve learning and memory of global cerebral ischemia rats, the mechanism of which might be that rTMS enhance the hippocampal theta and gamma oscillations and increase the expression of PKA and p-CREB protein in the hippocampus, thus increasing the hippocampus synaptic plasticity. Key words: Brain ischemia; Learning and memory; Repeated transcranial magnetic stimulation; Protein kinase A; cAMP-response element binding protein; Local field potential