Abrial Erika, Bétourné Alexandre, Etiévant Adeline, Lucas Guillaume, Scarna Hélène, Lambás-Señas Laura, Haddjeri Nasser
INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
Int J Neuropsychopharmacol. 2014 Oct 31;18(2):pyu031. doi: 10.1093/ijnp/pyu031.
Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania.
Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72 h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control.
We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD.
Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties.
近期研究表明，双相情感障碍可能与神经可塑性缺陷有关。此外，越来越多的证据表明细胞内信号分子蛋白激酶C（PKC）的改变与躁狂症有关。
本研究以睡眠剥夺（SD）作为躁狂症的动物模型，旨在探讨PKC与躁狂症中神经可塑性之间的可能关系。将大鼠进行72小时的睡眠剥夺并进行行为测试。同时，用溴脱氧尿苷（BrdU）标记评估睡眠剥夺诱导的海马细胞增殖变化。然后，我们研究了情绪稳定剂锂、抗精神病药物阿立哌唑以及PKC抑制剂白屈菜红碱和他莫昔芬对睡眠剥夺诱导的行为和细胞增殖损伤的影响。抗抑郁药氟西汀用作阴性对照。
我们发现睡眠剥夺引发了类似躁狂的行为，如运动亢进和睡眠潜伏期延长，并减少了海马细胞增殖。锂和阿立哌唑的急性给药可抵消这些改变，但氟西汀则不能，而且仅单次给予阿立哌唑就能增加细胞增殖。重要的是，睡眠剥夺的大鼠海马和前额叶皮质中磷酸化突触体相关蛋白25（SNAP - 25）水平升高，提示PKC过度活跃。此外，PKC抑制剂减轻了类似躁狂的行为，并挽救了睡眠剥夺诱导的细胞增殖缺陷。
我们的研究结果证实了睡眠剥夺作为躁狂症模型的相关性，并提供证据表明抗躁狂药物也能够预防睡眠剥夺诱导的海马细胞增殖减少。此外，研究结果强调了PKC抑制剂的治疗潜力，这体现在它们类似抗躁狂和促进增殖的特性上。
