Hajszan Tibor, Dow Antonia, Warner-Schmidt Jennifer L, Szigeti-Buck Klara, Sallam Nermin L, Parducz Arpad, Leranth Csaba, Duman Ronald S
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Biol Psychiatry. 2009 Mar 1;65(5):392-400. doi: 10.1016/j.biopsych.2008.09.031. Epub 2008 Nov 12.
Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications.
We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm.
Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects.
These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.
尽管多年来一直有假说认为抑郁症与突触丧失有关，主要发生在海马体，且抗抑郁药可促进突触生长，但我们仍缺乏超微结构证据表明抑郁行为的改变确实与突触结构修饰相关。
我们运用电子显微镜体视学分析了127只雄性大鼠的海马棘突触，并将其与习得性无助范式中的行为表现相关联。
不可逃避的足部电击（IES）导致CA1、CA3和齿状回中的棘突触急性且持续丧失，这与习得性无助中的严重逃避缺陷相关。另一方面，IES在运动皮层未引起明显的突触改变。单次注射皮质酮可重现IES诱导的海马突触变化和行为反应。用去甲丙咪嗪对遭受IES的动物进行6天治疗可逆转海马棘突触丧失以及习得性无助中的逃避缺陷。然而，我们注意到去甲丙咪嗪未能将CA1棘突触数量恢复到非应激水平，与非应激对照大鼠相比，这与轻微的逃避缺陷相关。然而，较短的1天或3天去甲丙咪嗪治疗既无突触效应也无行为效应。
这些结果表明，抑郁行为的改变与海马棘突触在超微结构水平上的显著重塑有关。由于棘突触丧失会导致海马功能障碍，这种细胞机制可能是抑郁症等应激相关疾病神经生物学中的一个重要组成部分。
