Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces.
Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces.
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DOI：
10.1038/srep43468
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发表时间：
2017-02-27
影响因子：
4.6
通讯作者：
Sánchez-Blázquez P
中科院分区：
文献类型：
--
作者：
Garzón-Niño J;Rodríguez-Muñoz M;Cortés-Montero E;Sánchez-Blázquez P
组氨酸三联体核苷酸结合蛋白1(HINT1)缺失的小鼠表现出躁狂样症状，并在应激模式下演变为抑郁样行为。分子和电生理学研究表明，HINT1NK3受体(NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic受体(AMPAR)和NR2B/NR2A亚单位比值、蛋白激酶C、蛋白激酶A和−/−的β活性增加。药物干预稳定了他们的行为，但机制不同。β抑制剂和丙戊酸可直接减轻躁狂样症状的表达，而蛋白激酶C抑制剂、拉莫三嗪或利培酮则促进NMDAR介导的抑郁样行为，以抵消先前存在的躁狂样症状。暴露在应激模式下的幼稚HINT1−/−小鼠在随后的应激情况下迅速表现出抑郁样行为，这种能力持续了几周。在抑郁样阶段，西酞普兰、阿米替林和MK801可诱发应激HINT1−/−小鼠的躁狂样行为。值得注意的是，NMDAR的拮抗作用阻止了HINT1−/−小鼠在应激反应中改变行为。与“躁狂”黑瑞士小鼠的比较表明，在HINT1−/−小鼠中，PKC支持躁狂样症状，并通过激活GSK3NMDAR和调节富含NR2B的NMDAR来减少抑郁样行为的表达。HINT1−/−小鼠代表了研究人类BPD的合适模型，并可能有助于识别治疗这种精神障碍的新靶点和药物。
Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1−/− mice exhibit increased PKC, PKA, and GSK3β activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3β inhibitors and valproate directly attenuated the expression of the manic-like symptoms, whereas PKC inhibition, lamotrigine, or risperidone promoted NMDAR-mediated depressive-like behaviors that counterbalanced the preexisting manic-like symptoms. Naïve HINT1−/− mice exposed to stressful paradigms rapidly manifested depressive-like behaviors in subsequent stressful situations, a capacity that persisted for a couple of weeks thereafter. During the depressive-like phase, citalopram, amitriptyline and MK801 precipitated manic-like behaviors in stressed HINT1−/− mice. Notably, the antagonism of NMDARs prevented HINT1−/− mice from alternating behaviors in response to stress. A comparison with “manic” Black Swiss mice indicated that in HINT1−/− mice, PKC supports manic-like symptoms and reduces the expression of depressive-like behaviors via activation of GSK3β and regulation of NR2B-enriched NMDARs. HINT1−/− mice represent a suitable model for studying human BPD and may facilitate the identification of novel targets and drugs to treat this mental disorder.