Center for Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Biol Psychiatry. 2010 Jun 1;67(11):1048-56. doi: 10.1016/j.biopsych.2010.01.024. Epub 2010 Mar 15.
Chronic but not acute treatment with antidepressants increases hippocampal neurogenesis. Because chronic treatment with antidepressants also upregulates p11, we hypothesized that p11 might regulate effects of antidepressants on aspects of neurogenesis.
Fluoxetine was administered chronically to wild-type (WT) and p11 knockout (KO) mice. In the neurogenic subgranular zone of hippocampus, the effects of fluoxetine on cell survival were examined with bromodeoxyuridine immunohistochemistry, whereas in the same brains cell proliferation was measured with Ki-67 immunohistochemistry, neurogenesis was measured with doublecortin immunohistochemistry, and apoptosis was measured with activated caspase-3. The behavioral action of fluoxetine was assessed in the novelty suppressed feeding test, which is considered neurogenesis-dependent. The localization of p11 in the dentate gyrus was studied with immunohistochemistry.
Vehicle-treated p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis relative to WT mice. In response to fluoxetine, p11 KO mice have reduced cell proliferation, neurogenesis, cell survival, and cell apoptosis in the subgranular zone of hippocampus when compared with WT littermates. P11 was not expressed in neurogenic cells but in different subtypes of neighboring gamma-aminobutyric acid (GABA)ergic interneurons, which also express serotonin 1B and serotonin 4 receptors. The behavioral effects of fluoxetine in the novelty suppressed feeding test were abolished in p11 KO mice.
P11 is abundantly expressed in hippocampal GABAergic interneurons. The p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis and an attenuated response to fluoxetine in measures of neurogenesis and in a neurogenesis-dependent behavioral test.
慢性而非急性抗抑郁治疗会增加海马神经发生。由于抗抑郁治疗也会上调 p11，我们假设 p11 可能调节抗抑郁药对神经发生各方面的作用。
用氟西汀对野生型（WT）和 p11 敲除（KO）小鼠进行慢性处理。在海马亚颗粒区的神经发生区，用溴脱氧尿苷免疫组织化学法检测氟西汀对细胞存活的影响，而在相同的大脑中，用 Ki-67 免疫组织化学法测量细胞增殖，用双皮质素免疫组织化学法测量神经发生，用激活的半胱天冬酶-3 测量细胞凋亡。用新颖性抑制进食测试评估氟西汀的行为作用，该测试被认为依赖于神经发生。用免疫组织化学法研究 p11 在齿状回中的定位。
与 WT 小鼠相比，未经处理的 p11 KO 小鼠的未成熟神经元细胞存活和神经发生标志物水平升高。与 WT 同窝仔鼠相比，p11 KO 小鼠在海马亚颗粒区的细胞增殖、神经发生、细胞存活和细胞凋亡减少。p11 不在神经发生细胞中表达，但在不同亚型的邻近γ-氨基丁酸（GABA）能中间神经元中表达，这些神经元也表达 5-羟色胺 1B 和 5-羟色胺 4 受体。在新颖性抑制进食测试中，氟西汀的行为作用在 p11 KO 小鼠中被消除。
p11 在海马 GABA 能中间神经元中大量表达。p11 KO 小鼠的未成熟神经元细胞存活和神经发生标志物水平升高，对氟西汀的神经发生和神经发生依赖性行为测试的反应减弱。
