Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model
Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model
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DOI：
10.1038/mp.2016.121
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发表时间：
2017-10-01
影响因子：
11
通讯作者：
Lodge, D. J.
中科院分区：
文献类型：
--
作者：
Donegan, J. J.;Tyson, J. A.;Lodge, D. J.
越来越多的文献表明，精神分裂症与海马中间神经元功能下降有关。因此，我们认为，干细胞衍生的中间神经元移植可能是一种有效的治疗策略，以减少海马活动过度和减轻精神分裂症的行为缺陷。在这里，我们使用了一个双报告胚胎干细胞系，以产生丰富的人口的小白蛋白（PV）或生长抑素（SST）阳性的中间神经元，这被移植到腹侧海马的methylazoxymethanol啮齿动物模型的精神分裂症。这些中间神经元移植整合在现有的电路，减少海马过度活跃和正常化异常多巴胺神经元的活动。此外，中间神经元移植减轻了模拟消极和认知症状的行为，包括社会互动和认知能力的缺陷。有趣的是，PV和SST富集移植对行为产生了不同的影响，PV富集群体有效地使所有检查的行为正常化。这些数据表明，干细胞衍生的中间神经元移植可能代表精神分裂症的一种新的治疗策略。
An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)-or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV-and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.