Gestational Choline Levels and Sensory Inhibition

描述（由申请人提供）：感觉抑制缺陷是精神分裂症的常见症状，并与某些阳性症状相关。症状的改善与感觉抑制的改善同时出现。在DBA/2小鼠中建立了感觉抑制缺陷模型，它不仅表现出感觉抑制缺陷，而且在海马α 7烟碱受体数量减少和基因编码多态性方面也与精神分裂症患者相似。我们最近的研究表明，围产期在饲料中添加胆碱，可以产生具有正常感觉抑制的DBA/2后代。在大鼠和一种小鼠品系（C57/BL6）中，围产期补充胆碱已被证明可以改善后代一生的学习和记忆能力。我们的初步数据显示，感觉抑制回路也发生了永久性的改变，在围出生期补充胆碱后，齿状回和海马CA1区域的apha7烟碱受体显著增加。改善感觉抑制的潜在机制尚不清楚。目前的申请将试图通过评估α /受体的作用（使用alpha7零突变小鼠），非alpha7受体的作用（使用alpha7和非alpha7受体的激动剂，与alpha7受体的激动剂相比，alpha7受体也是alpha4beta2受体的拮抗剂），以及DNA甲基化的作用（使用替代甲基供体，另外，使用具有高甲基化的基因改变小鼠品系）来阐明机制。由于学习和记忆的影响已经观察到围产期胆碱管理，所有组将测试学习和记忆的改变。最后，任何围产期干预和高甲基化小鼠诱导的海马α 7受体水平的变化将使用定量放射自显影术进行评估。来自这些研究的数据可能会潜在地影响精神分裂症高危妊娠的人类产前营养指南。

DESCRIPTION (provided by applicant): Deficits in sensory inhibition are a common symptom of schizophrenia and are correlated with certain positive symptoms. Improvement in symptomology is seen concurrent with improvement in sensory nhibition. The sensory inhibition deficit has been modeled in DBA/2 mice which not only show the deficient sensory inhibition, but are also genotypically similar to schizophrenics in having reduced numbers of alpha7 nicotinic receptors in the hippocampus and polymorphisms in the gene coding. We have recently shown that perinatal choline supplementation in the diet of the dam, produces DBA/2 offpspring with normal sensory nhibition. Perinatal choline supplementation in rats and one mouse strain (C57/BL6) has previously been shown to improve learning and memory in offspring thoughout their lifetimes. Our preliminary data show that sensory inhibition circuitry is also permanently altered in that there is a significant increase in apha7 nicotinic receptors in the dentate gyrus and CA1 regions of the hippocampus with peri-natal choline supplementation. The underlying mechanism of the improved sensory inhibition is not known. The present application will seek to elucidate the mechanism(s) by assessing role of alpha/ receptors (using alpha7 null mutant mice), the role of non-alpha7 receptors (using an agonist at both alpha7 and non-alpha7 receptors compared to an agonist at alpha7 receptors which is also an antagonist at alpha4beta2 receptors), and the role of DNA methylation (using an alternate methyl donor, and additionally, a genetically altered mouse strain with hypermethylation). Since learning and memory effects have been observed with peri-natal choline administration, all groups will be tested for learning and memory alterations. Finally, any changes in hippocampal alpha7 receptor levels induced by any of the perinatal interventions as well as the hypermethylation mice mice will be assessed using quantitative autoradiography. The data from these studies may potentially impact guide lines for human prenatal nutrition in at-risk pregnancies for schizophrenia.