Elucidation of pathophysiology of refractory depression and development of newer treatment based on the disturbance of spine dynamics

本研究旨在探讨海马棘突异常引起的突触密度降低是否与难治性抑郁症的病理生理有关。我们利用新生儿隔离和习得性无助建立了难治性抑郁症大鼠模型。本研究的主要发现是：1）模型大鼠海马中树突棘的棘长度增加，棘密度无任何变化，2）脑源性神经营养因子（BDNF）的免疫反应性降低，3）microRNA（miR）-132水平降低，4）miR-134水平不受影响，5）TrkB免疫反应性降低。这些发现表明，由于海马中BDNF-TrkB信号降低而导致的脊柱异常可能参与难治性抑郁症的病理生理学，通过来自BDNF基因3'区域的miR调节下调BDNF的贡献较小。

The present study was undertaken to examine whether the decreased synaptic density through the spine abnormality in the hippocampus is involved in the pathophysiology of refractory depression. We developed a rat model of refractory depression using neonatal isolation and learned helplessness. The principal findings of this study were that 1) the spine length of dendritic spines was longer in the hippocampus of the model rats without any changes in spine density, 2) the immunoreactivity of brain-derived neurotrophic factor (BDNF) was decreased, 3) the levels of microRNA (miR)-132 were decreased, 4) the levels of miR-134 were not affected, 5) the immunoreactivity of TrkB was decreased. These findings suggested that the spine abnormality due to the decreased BDNF-TrkB signal in the hippocampus may be involved in the pathophysiology of refractory depression, with less contribution by downregulation of BDNF through miR regulation from the 3' region of the BDNF gene.