Departments of Pharmacology, Georgetown University Medical Center, Washington, District of Columbia, USA.
Departments of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA.
J Neurochem. 2019 Mar;148(6):810-821. doi: 10.1111/jnc.14671. Epub 2019 Feb 20.
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: 10.1111/jnc.14498.
靶向单胺能传递的药物是治疗重度抑郁症的一线治疗方法。尽管人们对抗抑郁疗效的机制还没有完全了解，但有证据表明增强兴奋性传递发挥了作用。这种作用可能通过两种非互斥的机制产生。第一种机制涉及通过相对直接的机制增强兴奋性神经元的功能，例如增强树突分支。另一种机制涉及抑制功能的降低，这种情况发生在快速抗抑郁药氯胺酮中。与这种情况一致的是，GABA 能中间神经元介导的皮质抑制与减少的γ振荡功率有关，这种节律在抑郁症中也减少。抑郁症状的缓解与γ功率的恢复相关。由于强大的兴奋性输入、可靠的 GABA 释放和快速放电，表达 PV 的神经元（PV 神经元）是同步振荡的关键起搏器。PV 神经元也是被神经周围网络（PNNs）包围的主要 GABA 能神经元群体，PNNs 是一种网格状结构，可使谷氨酸能输入本地化。PNNs 的破坏会降低 PV 的兴奋性并增强 γ 活性。研究表明，单胺再摄取抑制剂会降低 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得到探索。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，5-羟色胺/去甲肾上腺素再摄取抑制剂文拉法辛通过 ELISA 确定增加了海马基质金属蛋白酶（MMP）-9 水平，并通过分析用荧光 PNN 结合凝集素染色后的切片来同时降低了小鼠海马中的 PNN 完整性。此外，用文拉法辛（30mg/kg/天）治疗的小鼠在离体海马切片中显示出 carbachol 诱导的γ功率增加，这是通过局部场电位记录和 Matlab 分析确定的。在基质金属蛋白酶 9（MMP-9）缺乏的小鼠中进行的研究表明，MMP-9 与其他情况下的 PNN 破坏有关，这表明 MMP-9 有助于文拉法辛增强的γ功率。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药的疗效，而 PNN 的影响可能会增强与情绪和/或记忆相关的神经元群体动力学。本期的封面图片：doi：10.1111/jnc.14498。
