Mansouri Shiva, Agartz Ingrid, Ögren Sven-Ove, Patrone Cesare, Lundberg Mathias
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
PLoS One. 2017 Jan 26;12(1):e0170496. doi: 10.1371/journal.pone.0170496. eCollection 2017.
Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.
氯胺酮给药是一种成熟的方法，用于在实验中模拟精神分裂症的某些方面。成年神经发生失调与包括精神分裂症在内的精神疾病有关。神经发生在氯胺酮诱导的表型中的潜在作用在很大程度上尚不清楚。人类遗传学研究的最新结果表明，垂体腺苷酸环化酶激活多肽（PACAP）基因是精神分裂症的一个危险因素。其在精神分裂症实验模型中对神经发生调节的潜在作用仍有待研究。我们旨在确定氯胺酮是否会影响成年神经干细胞（NSC）的活力。我们还研究了PACAP是否可以抵消氯胺酮介导的有害作用。从小鼠脑室下区分离出神经干细胞，并将其暴露于含或不含PACAP的氯胺酮中。24小时后，通过定量RT-PCR和蛋白质印迹分析评估细胞活力、凋亡的潜在参与、内质网（ER）应激、mTOR和AMPA途径激活情况。我们发现氯胺酮损害神经干细胞活力，这与凋亡增加、内质网应激和mTOR激活相关。结果还表明，氯胺酮的作用是通过AMPA受体激活发生的。最后，我们表明PACAP通过特异性激活PAC-1受体亚型抵消了氯胺酮诱导的神经干细胞活力下降。我们的研究表明，氯胺酮可能会对神经干细胞活力产生负面影响，这对氯胺酮诱导的精神分裂症动物模型中精神分裂症表型的发展具有重要意义。通过PAC-1激活产生的神经保护作用表明，通过使神经发生正常化，可能为精神分裂症的治疗提供一个新的药理学靶点。
