Entorhinal Transcriptome in Schizophrenia

描述（由申请人提供）：颞叶，包括海马体，下托和内嗅皮层（EC）是与精神分裂症相关的主要大脑区域之一。EC是信息流向海马体的管道的一个组成部分，有助于调节皮层-海马体-皮层下的相互作用。在精神分裂症的神经病理学研究中，已经描述了EC的ll/ll层星状神经元的各种异常，包括异常的细胞结构排列、较小的神经元大小、细胞骨架蛋白MAP2的表达减少、谷氨酸能神经支配的改变以及转录因子、突触蛋白和嗜电性谷氨酸受体亚基等mrna的差异表达。EC的战略位置和先前在该区域确定的生物学相关性使EC成为探索与精神分裂症相关的基因表达疾病相关差异的绝佳候选者。对死后人体组织的研究已经确定了欧共体和其他大脑区域基因表达的改变；然而，仍有几个问题有待研究：1)与精神分裂症相关的大脑区域的全基因组探索；2)目标神经元群体的表达谱与其他神经元和非神经元群体中发生的变化之间缺乏区分；3)精神分裂症基因表达谱与灵长类动物大脑中抗精神病药物史相关的基因表达谱的分化。为此，我们将使用来自精神分裂症患者EC的人类死后组织，并使用斯坦利医学研究基金会收集的阵列来比较双相情感障碍的变化。这将在区域层面以及在EC的第2 / 3层和第5层神经元内完成。进一步的研究将探索来自宾夕法尼亚大学脑库的一组精神分裂症患者的定义变化。此外，还将比较人类死后组织与服用6个月抗精神病药物后从恒河猴身上获得的组织。迄今为止，治疗方案、尸检和组织采集已经完成，可用新鲜冷冻和石蜡包埋的EC。

DESCRIPTION (provided by applicant): The temporal lobe, including the hippocampus, subiculum and entorhinal cortex (EC) is one of the primary brain regions associated with schizophrenia. EC is an integral component of the conduit through which information flows to the hippocampus, helping regulate cortical-hippocampal-subcortical interactions. Various abnormalities in Layer ll/lll stellate neurons of the EC have been described in neuropathologic studies of schizophrenia, including aberrant cytoarchitectural arrangement, smaller neuron size, decreased expression of the cytoskeletal protein MAP2, altered glutamatergic innervation and differential expression of a number of mRNAs including transcription factors, synaptic proteins, and ionotropic glutamate receptor subunits. The strategic location of the EC and the previously identified biological correlates in this region make the EC an excellent candidate for probing disease-related differences in gene expression associated with schizophrenia. Studies in post-mortem human tissue have identified alterations in gene expression in the EC and other brain regions; however, several issues remain to be investigated: 1) whole genome exploration of brain regions implicated in schizophrenia and 2) lack of discernment between expression profiles in target neuronal populations and changes occurring in other neuronal and non-neuronal populations, and 3) differentiation of gene expression profiles from schizophrenia versus profiles attributable to antipsychotic drug history in primate brain. To this end, we will use human post mortem tissue from the EC of schizophrenics and compare changes to bipolar disorder using the array collection from the Stanley Medical Research Foundation. This will be accomplished at the regional level and within Layer ll/lll and Layer V neurons in the EC. Additional studies will explore the defined changes in a cohort of schizophrenics from the UPENN brain bank. In addition, comparisons will be made between the human post-mortem tissue and tissue acquired from rhesus monkeys following six month antipsychotic administration. To date, the treatment regimen, necropsy and tissue harvesting have been completed with both fresh frozen and paraffin-embedded EC available.