Gestational Choline Levels and Sensory Inhibition

描述(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是同步进行的。在DBA/2小鼠中已经建立了感觉抑制缺陷的模型，不仅表现出感觉抑制的缺陷，而且在海马区α7尼古丁受体数量减少和基因编码的多态方面与精神分裂症患者具有典型的相似之处。我们最近的研究表明，围产期补充胆碱能产生DBA/2后代，并具有正常的感觉抑制。在大鼠和一种小鼠品系(C57/BL6)中，围产期补充胆碱之前已经被证明可以改善后代的学习和记忆，尽管他们的一生都是如此。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，在出生前补充胆碱的情况下，海马齿状回和CA1区的APHA7尼古丁受体显着增加。改善感觉抑制的潜在机制尚不清楚。本申请将试图通过评估α/受体的作用(使用alpha7缺失突变小鼠)、非alpha7受体的作用(使用alpha7和非alpha7受体的激动剂与同时使用alpha7受体的激动剂和同时也是alpha4beta2受体的拮抗剂的alpha7受体激动剂)以及DNA甲基化的作用(使用替代甲基供体，以及另外，使用具有超甲基化的基因改变的小鼠品系)来阐明该机制(使用alpha7缺失突变小鼠)。由于已观察到围产期服用胆碱对学习和记忆的影响，所有组都将接受学习和记忆改变的测试。最后，任何围产期干预措施以及高甲基化小鼠所引起的海马区α7受体水平的任何变化都将通过定量放射自显影进行评估。这些研究的数据可能会潜在地影响人类精神分裂症高危妊娠的产前营养指南。

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.