HPC-1/syntaxin 1A gene knockout mice show abnormal behavior possibly related to a disruption in 5-HTergic systems
HPC-1/syntaxin 1A gene knockout mice show abnormal behavior possibly related to a disruption in 5-HTergic systems
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DOI：
10.1111/j.1460-9568.2010.07269.x
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发表时间：
2010-07-01
影响因子：
3.4
通讯作者：
Akagawa, Kimio
中科院分区：
文献类型：
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作者：
Fujiwara, Tomonori;Snada, Masumi;Akagawa, Kimio
HPC-1/syntaxin 1A（STX 1A）被认为调节神经元中突触囊泡的胞吐作用。在最近的人类遗传学研究中，STX 1A与神经心理障碍有关。为了研究STX 1A基因消融是否是人类精神病患者中观察到的异常神经心理学特征的原因，我们分析了STX 1A基因敲除小鼠的行为表型。在社会互动测试、新物体探索测试和潜伏抑制（LI）测试中，在纯合子（STX 1A-/-）和杂合子（STX 1A +/-）中均观察到异常行为，但在前脉冲抑制测试中未观察到异常行为。有趣的是，LI的衰减，这是密切相关的人的神经元型症状，恢复管理的选择性5-羟色胺再摄取抑制剂，氟西汀，但不是由多巴胺再摄取抑制剂，GBR 12935，或去甲肾上腺素再摄取抑制剂，地昔帕明。我们还观察到DOI（一种5-HT（2A）受体激动剂）可恢复LI衰减，但8-OH-DPAT（一种5-HT（1A）受体激动剂）、mCPP（一种5-HT（2C）受体激动剂）、SKF 38393（一种D（1）受体激动剂）、喹吡罗（一种D（2）/D（3）受体激动剂）或氟哌啶醇（一种D（2）/D（3）受体拮抗剂）不能恢复LI衰减。因此，LI的衰减主要是通过5-HT（2A）受体破坏5-HT能系统引起的。此外，海马和下丘脑脑片的5-HT释放显著减少。因此，STX 1A的消融可能会导致5-HT能传递中断并诱导异常行为。
HPC-1/syntaxin 1A (STX1A) is thought to regulate the exocytosis of synaptic vesicles in neurons. In recent human genetic studies, STX1A has been implicated in neuropsychological disorders. To examine whether STX1A gene ablation is responsible for abnormal neuropsychological profiles observed in human psychiatric patients, we analysed the behavioral phenotype of STX1A knockout mice. Abnormal behavior was observed in both homozygotes (STX1A-/-) and heterozygotes (STX1A+/-) in a social interaction test, a novel object exploring test and a latent inhibition (LI) test, but not in a pre-pulse inhibition test. Interestingly, attenuation of LI, which is closely related to human schizotypic symptoms, was restored by administration of the selective serotonin reuptake inhibitor, fluoxetine, but not by the dopamine reuptake inhibitor, GBR12935, or the noradrenalin reuptake inhibitor, desipramine. We also observed that LI attenuation was restored by DOI (a 5-HT(2A) receptor agonist), but not by 8-OH-DPAT (a 5-HT(1A) receptor agonist), mCPP (a 5-HT(2C) receptor agonist), SKF 38393 (a D(1) receptor agonist), quinpirole (a D(2)/D(3) receptor agonist) or haloperidol (a D(2)/D(3) receptor antagonist). Thus, attenuation of LI is mainly caused by disruption of 5-HT-ergic systems via 5-HT(2A) receptors. In addition, 5-HT release from hippocampal and hypothalamic slices was significantly reduced. Therefore, ablation of STX1A may cause disruption of 5-HT-ergic transmission and induce abnormal behavior.