Venlafaxine stimulates PNN proteolysis and MMP-9-dependent enhancement of gamma power; relevance to antidepressant efficacy
Venlafaxine stimulates PNN proteolysis and MMP-9-dependent enhancement of gamma power; relevance to antidepressant efficacy
复制标题
DOI：
10.1111/jnc.14671
复制
发表时间：
2019-03-01
影响因子：
4.7
通讯作者：
Conant, Katherine
中科院分区：
文献类型：
--
作者：
Alaiyed, Seham;Bozzelli, P. Lorenzo;Conant, Katherine
靶向单胺能传递的药物是治疗重度抑郁症的一线药物。虽然对抗抑郁药疗效的机制缺乏充分的了解，但证据支持增强兴奋传递的作用。这可以通过两种不相互排斥的机制实现。第一种涉及通过相对直接的机制，如增强树突树突，增加兴奋性神经元的功能。另一种机制涉及抑制功能的降低，这与快速抗抑郁药氯胺酮有关。与此一致的是，伽马氨基丁酸能中间神经元介导的皮层抑制与伽马振荡功率降低有关，这种节律在抑郁症中也会减弱。抑郁症状的缓解与伽马能量的恢复相关。由于强兴奋性输入、可靠的GABA释放和快速放电，PV表达神经元（PV神经元）是同步振荡的关键起搏器。PV神经元也代表了主要的gaba能群体，被神经周围网（pnn）包围，pnn是定位谷氨酸能输入的晶格状结构。PNNs的破坏降低了PV的兴奋性并增强了γ活性。研究表明，单胺再摄取抑制剂可降低PNN的完整性。然而，这些抑制剂降低PNN完整性的机制在很大程度上仍未被探索。更好地了解这些问题可能会鼓励开发出最好地上调pnn调节蛋白酶的治疗方法。我们观察到，血清素/去甲肾上腺素再摄取抑制剂文拉法辛增加了海马基质金属蛋白酶(MMP)-9的水平，同时通过荧光PNN结合凝集素染色后的切片分析发现，文拉法辛降低了小鼠海马PNN的完整性。此外，通过局部场电位记录和Matlab分析，文拉法辛处理的小鼠（30 mg/kg/天）在离体海马切片中显示出碳巴酚诱导的伽马功率增加。基质金属蛋白酶9 （MMP-9）是一种在其他情况下与PNN破坏相关的蛋白酶，对缺乏基质金属蛋白酶9的小鼠进行的研究表明，MMP-9有助于文拉法辛增强γ能量。总之，我们的研究结果支持这样一种可能性，即MMP-9活性通过对PNN的影响来促进抗抑郁疗效，而PNN可能反过来增强与情绪和/或记忆有关的神经元群体动态。本期封面图片：doi：。
Drugs that target monoaminergic transmission represent a first-line treatment for major depression. Though a full understanding of the mechanisms that underlie antidepressant efficacy is lacking, evidence supports a role for enhanced excitatory transmission. This can occur through two non-mutually exclusive mechanisms. The first involves increased function of excitatory neurons through relatively direct mechanisms such as enhanced dendritic arborization. Another mechanism involves reduced inhibitory function, which occurs with the rapid antidepressant ketamine. Consistent with this, GABAergic interneuron-mediated cortical inhibition is linked to reduced gamma oscillatory power, a rhythm also diminished in depression. Remission of depressive symptoms correlates with restoration of gamma power. As a result of strong excitatory input, reliable GABA release, and fast firing, PV-expressing neurons (PV neurons) represent critical pacemakers for synchronous oscillations. PV neurons also represent the predominant GABAergic population enveloped by perineuronal nets (PNNs), lattice-like structures that localize glutamatergic input. Disruption of PNNs reduces PV excitability and enhances gamma activity. Studies suggest that monoamine reuptake inhibitors reduce integrity of the PNN. Mechanisms by which these inhibitors reduce PNN integrity, however, remain largely unexplored. A better understanding of these issues might encourage development of therapeutics that best up-regulate PNN-modulating proteases. We observe that the serotonin/norepinephrine reuptake inhibitor venlafaxine increases hippocampal matrix metalloproteinase (MMP)-9 levels as determined by ELISA and concomitantly reduces PNN integrity in murine hippocampus as determined by analysis of sections following their staining with a fluorescent PNN-binding lectin. Moreover, venlafaxine-treated mice (30 mg/kg/day) show an increase in carbachol-induced gamma power in ex vivo hippocampal slices as determined by local field potential recording and Matlab analyses. Studies with mice deficient in matrix metalloproteinase 9 (MMP-9), a protease linked to PNN disruption in other settings, suggest that MMP-9 contributes to venlafaxine-enhanced gamma power. In conclusion, our results support the possibility that MMP-9 activity contributes to antidepressant efficacy through effects on the PNN that may in turn enhance neuronal population dynamics involved in mood and/or memory. Cover Image for this issue: doi: .