A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: Implications for the neuropathology of schizophrenia
A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: Implications for the neuropathology of schizophrenia
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DOI：
10.1016/j.biopsych.2006.01.003
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发表时间：
2006-08-01
影响因子：
10.6
通讯作者：
Grace, Anthony A.
中科院分区：
文献类型：
--
作者：
Moore, Holly;Jentsch, J. David;Grace, Anthony A.
这些研究检查了在大鼠胚胎期(E) 17开始的大脑发育中断，使用甲基化剂甲基氧乙酸甲醇（MAM），是否会导致精神分裂症相关的神经和行为病理模式。具体来说，我们测试了这种操作是否会导致额叶和边缘皮质纹状体回路功能的中断，同时产生类似精神分裂症的、区域依赖性的皮层和丘脑灰质减少。方法：在E17 （E15）及之前给药MAM （22 mg/kg）的大鼠子代，测定其多脑区面积、神经元数量和神经元密度。在体内记录了前额皮质（PFC）和腹侧纹状体（vSTR）神经元的自发突触活动。最后，评估了由额叶和边缘皮质纹状体回路介导的认知和感觉运动过程。暴露于mam - e17的成年后代表现出选择性的组织病理学：丘脑中背侧、海马、海马旁、前额叶和枕叶皮质的尺寸减小，但感觉中脑、小脑或感觉运动皮质的尺寸减小。前额叶、鼻周和枕叶皮层神经元密度增加，但未见神经元丢失。组织病理学表现为PFC和vSTR神经元中突触驱动的“双稳态膜状态”的破坏，在行为水平上，表现为认知不灵活性、口面部运动障碍、感觉运动门控缺陷和青春期后出现的对安非他明的高反应。早期的胚胎MAM暴露导致小头畸形和运动表型。结论：“MAM-E17”啮齿类动物模拟了与精神分裂症高度相关的神经回路中神经病理学的关键方面。
cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus.Methods: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prqfrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed.Results. Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parabippocampal, prqfrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motorphenotype.Conclusions: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.