Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; and
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; and.
Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):E2492-500. doi: 10.1073/pnas.1323287111. Epub 2014 Jun 2.
Maternal infection during pregnancy increases the risk for schizophrenia in offspring. In rodent models, maternal immune activation (MIA) yields offspring with schizophrenia-like behaviors. None of these behaviors are, however, specific to schizophrenia. The presence of hallucinations is a key diagnostic symptom of schizophrenia. In mice, this symptom can be defined as brain activation in the absence of external stimuli, which can be mimicked by administration of hallucinogens. We find that, compared with controls, adult MIA offspring display an increased stereotypical behavioral response to the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), an agonist for serotonin receptor 2A (5-HT2AR). This may be explained by increased levels of 5-HT2AR and downstream signaling molecules in unstimulated MIA prefrontal cortex (PFC). Using manganese-enhanced magnetic resonance imaging to identify neuronal activation elicited by DOI administration, we find that, compared with controls, MIA offspring exhibit a greater manganese (Mn(2+)) accumulation in several brain areas, including the PFC, thalamus, and striatum. The parafascicular thalamic nucleus, which plays the role in the pathogenesis of hallucinations, is activated by DOI in MIA offspring only. Additionally, compared with controls, MIA offspring demonstrate higher DOI-induced expression of early growth response protein 1, cyclooxygenase-2, and brain-derived neurotrophic factor in the PFC. Chronic treatment with the 5-HT2AR antagonist ketanserin reduces DOI-induced head twitching in MIA offspring. Thus, the MIA mouse model can be successfully used to investigate activity induced by DOI in awake, behaving mice. Moreover, manganese-enhanced magnetic resonance imaging is a useful, noninvasive method for accurately measuring this type of activity.
母体怀孕期间的感染会增加后代患精神分裂症的风险。在啮齿动物模型中，母体免疫激活（MIA）会导致后代出现类似精神分裂症的行为。然而，这些行为都没有特异性地指向精神分裂症。幻觉的存在是精神分裂症的一个关键诊断症状。在小鼠中，这种症状可以被定义为在没有外部刺激的情况下大脑的激活，这可以通过施用致幻剂来模拟。我们发现，与对照组相比，成年 MIA 后代对致幻剂 2,5-二甲氧基-4-碘苯丙胺（DOI）表现出增加的刻板行为反应，DOI 是血清素受体 2A（5-HT2AR）的激动剂。这可以通过未受刺激的 MIA 前额叶皮层（PFC）中 5-HT2AR 和下游信号分子水平的增加来解释。使用锰增强磁共振成像来识别 DOI 给药引起的神经元激活，我们发现，与对照组相比，MIA 后代在几个脑区（包括前额叶皮层、丘脑和纹状体）中表现出更大的锰（Mn(2+)）积累。旁中央丘脑核在幻觉的发病机制中起作用，只有在 MIA 后代中 DOI 才会激活该核。此外，与对照组相比，MIA 后代在 PFC 中表现出更高的 DOI 诱导的早期生长反应蛋白 1、环氧化酶-2 和脑源性神经营养因子的表达。5-HT2AR 拮抗剂酮色林的慢性治疗可减少 MIA 后代 DOI 诱导的头部抽搐。因此，MIA 小鼠模型可成功用于研究清醒、行为活跃的小鼠中 DOI 诱导的活性。此外，锰增强磁共振成像是一种有用的、非侵入性的方法，可用于准确测量这种类型的活性。
