Cognitive impairment is induced by BDNF-TrkB signaling mediating synaptic damage and reduction of amino acid neurotransmitters in heart failure rats

Abstract

AbstractBackground Heart failure (HF) is often accompanied by cognitive impairment (CI). Yet, the underlying molecular mechanism is still not fully understood. Methods A HF model was prepared by ligation of the anterior descending coronary artery of the rat for 8 weeks. Echocardiography and morris water maze were performed to evaluate cardiac and cognitive function. Electron microscopy was conducted to quantify postsynaptic density (PSD) thickness, length, and cleft width of synapses. Thirteen neurotransmitters were detected by high-performance liquid chromatography, and proteins associated with the BDNF-TrkB pathway were determined by Western blot. The intervention of BDNF siRNA in fetal rat cortical neurons was chosen for further validation of the BDNF-TrkB pathway. Results HF rats passed through the original platform position in the probe trials fewer times and took more time and distance to reach the platform in the reversal phase compared with Sham rats; also, they had reduced thickness and length of PSD and increased synaptic cleft width. Expression of BDNF, TrkB, PSD95, and VGLUT1 was significantly decreased in HF rats brain. In addition, compared with Sham rats, amino acids were significantly reduced with no changes in the acetylcholine and monoamine neurotransmitters. Further examination showed that the number of synaptic bifurcation and the expression of BDNF, TrkB, PSD95, and VGLUT1 were all decreased in the neurons that interfered with BDNF-siRNA compared with those in the negative control neurons. Conclusions These data suggest that CI in HF is regulated by BDNF-TrkB signaling, mediating synaptic damage and reduction of amino acid neurotransmitters.