Selective ablation of type 3 adenylyl cyclase in somatostatin-positive interneurons produces anxiety- and depression-like behaviors in mice.
Selective ablation of type 3 adenylyl cyclase in somatostatin-positive interneurons produces anxiety- and depression-like behaviors in mice.
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DOI：
10.5498/wjp.v11.i2.35
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发表时间：
2021-02-19
影响因子：
3.1
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Yang XY;Ma ZL;Storm DR;Cao H;Zhang YQ
重度抑郁症（MDD）是一种高度致残的精神综合征，与皮质GABA能中间神经元的特定亚群缺陷相关;然而，其潜在的分子机制仍不清楚。3型腺苷酸环化酶（ADCY 3，AC 3）对神经元兴奋性很重要，在人类全基因组关联研究中与MDD有关。此外，一项研究报告称，在小鼠中消融AC 3会引起与MDD患者相似的症状。确定小鼠GABA能中间神经元不同亚型中AC 3基因的破坏是否导致抑郁样行为。利用免疫组织化学方法，我们研究了AC 3在两种主要亚型GABA能中间神经元中的表达：生长抑素阳性（SST+）和小清蛋白阳性（PV+）神经元。使用遗传操作来选择性地破坏SST+或PV+中间神经元中的AC 3表达。采用转棒试验、旷场试验、高架十字迷宫试验、强迫游泳试验、悬尾试验等一系列行为学测试，分别评价大鼠的运动能力、焦虑和抑郁样行为。我们的研究结果表明，大约90.41%的SST+和91.22%的PV+中间神经元表达AC 3。在SST+中间神经元中的AC 3消融后，小鼠在OFT中的中心区域花费相当的时间，但在开放臂中的时间显著更少，并且进入开放臂的频率低。此外，这些小鼠在FST中表现出延长的不动性，在TST中表现出更多的冻结。然而，在PV+中间神经元中特异性破坏AC 3后，这些行为没有显著变化。这项研究表明，小鼠SST+中间神经元中AC 3的消融增加了小鼠的焦虑和抑郁样行为，支持AC 3活性降低可能在人类抑郁症中发挥作用的一般假设。
Major depressive disorder (MDD) is a highly disabling psychiatric syndrome associated with deficits of specific subpopulations of cortical GABAergic interneurons; however, the underlying molecular mechanism remains unknown. Type 3 adenylyl cyclase (ADCY3, AC3), which is important for neuronal excitability, has been implicated in MDD in a genome-wide association study in humans. Moreover, a study reported that ablation of AC3 in mice caused similar symptoms as MDD patients. To determine if disruption of the AC3 gene in different subtypes of GABAergic interneurons of mice causes depression-like behaviors. Using immunohistochemistry, we investigated the expression of AC3 in two major subtypes GABAergic interneurons: Somatostatin-positive (SST+) and parvalbumin-positive (PV+) neurons. Genetic manipulations were used to selectively disrupt AC3 expression in SST+ or PV+ interneurons. A series of behavior tests including rotarod test, open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) were used to evaluate the motor ability, anxiety- and depression- like behaviors, respectively. Our results indicate that approximately 90.41% of SST+ and 91.22% of PV+ interneurons express AC3. After ablation of AC3 in SST+ interneurons, the mice spent comparable time in the center area in OFT, but significantly less time in the open arms and low frequency of entries to the open arms in EPM. Furthermore, these mice showed prolonged immobility in FST and more freezing in TST. However, there were no significant changes in these behaviors after specific disruption of AC3 in PV+ interneurons. This study indicates that ablation of AC3 in SST+ interneurons of mice increases anxiety- and depression-like behaviors in mice, supporting the general hypothesis that decreased AC3 activity may play a role in human depression.
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