Apoptosis in GABA Cells in Hippocampal Circuitry

海马回路 GABA 细胞凋亡

• 批准号: 7161941
• 负责人: JOSEPH T. COYLE
• 金额: --
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161941
• 关键词: amygdala; apoptosis; calcium channel; corticosterone; disease /disorder model; electrophysiology; environmental stressor; gamma aminobutyrate; glutamate receptor; hippocampus; in situ hybridization; inhibitor /antagonist; laboratory rat; laser capture microdissection; long term potentiation; neural information processing; picrotoxin; polymerase chain reaction; schizophrenia

We have developed a rodent model for neural circuitry changes in postmortem studies of the limbic lobe in schizophrenia (SZ). Based on observations that there is a preponderance of abnormalities in layer II of anterior cingulate cortex and sectors CA3/2 of hippocampus (HIPP) in SZs and both these sites receive an abundant projection from the basolateral amygdala (BLn), we have postulated that this nucleus may play a role in the induction of abnormalities in ACCx-ll and CA3/2 of SZs and bipolars (BDs). By stereotaxically infusing the non-competitive GABAA antagonist, picrotoxin (PICRO), into the basolateral amygdala (BLn), we have observed changes in GABAergic neurons in the HIPP remarkably similar to those seen in SZ. These studies have demonstrated that acute administration of PICRO results in complex changes of various subtypes of GABAergic neurons, particularly those in sectors CA3/2. Using gene expression profiling (GEP), we have reported that PICRO-treated rats show significant changes in several biologically relevant clusters of genes that include monoamine and peptide G-coupled protein (GPCRs) and apoptosis, that overlap with those showing changes in SZ and BD. In addition, to increased expression of the D4 receptor, as well as pro-apoptotic changes in BAX, c-myc and Bcl-2, we have also observed changes in the regulation of the L-Type calcium channel-ID (L-VGCC-1D) in both postmortem studies and in the rodent model. These genes show changes in expression not only in the HIPP of rats receiving acute or chronic infusion of PICRO on the BLn, but also in the HIPP of SZs and BDs. This overlap in gene expression profiling data across rat and human studies suggests that this model is a) valid, b) the data obtained are reliable, and c) those observed in humans may be related to the activation of the amygdalo-HIPP pathway that occurs in relation to environmental stress. In addition to the above target genes, we will also study the expression of subunits associated with NMDA (NR2A), AMPA (GluR1) and kainite (GluR6) receptors, since many postmortem studies have demonstrated evidence of a down-regulation of these glutamate receptors in SZ and excitotoxicity has been implicated in neuronal dysfunction in both SZ and BD. The subunits chosen show decreased expression in the chronic PICRO model and in patients with psychotic disorders. In the proposed experiments, a chronic infusion paradigm (4 wks continuous infusion of PICRO) will be used together with systemic administration of corticosterone (CORT) to simulate the conditions that might occur in the HIPP in response to environmental stress. We will test the hypothesis that amygdalar activation of the HIPP results in apoptotic changes in GABA cells, ones that are mediated via glutamate receptors and calcium channel activity.

我们已经建立了一个啮齿动物模型，用于研究死后边缘叶的神经回路变化， 精神分裂症（SZ）。根据观察，在第二层的异常占优势， 前扣带皮层和海马CA 3/2区（HIPP），这两个部位都接受了 由于基底外侧杏仁核（BLn）有丰富的投射，我们推测该核可能在杏仁核中起作用。 在诱导SZ和双极（BD）的ACCx-II和CA 3/2异常中的作用。通过立体定位 将非竞争性GABAA拮抗剂印防己毒素（PICRO）注入基底外侧杏仁核（BLn）， 我们观察到HIPP中GABA能神经元的变化与SZ中所见的变化非常相似。 这些研究表明，PICRO的急性给药导致各种 GABA能神经元的亚型，特别是在CA 3/2区的那些。使用基因表达谱（GEP）， 我们已经报道了PICRO处理的大鼠在几个生物学相关的集群中显示出显著的变化， 包括单胺和肽G偶联蛋白（GPCR）和凋亡的基因，与 显示SZ和BD变化的那些。此外，增加D4受体的表达，以及 在BAX、c-myc和Bcl-2的促凋亡变化中，我们还观察到L型凋亡调节的变化。 钙通道ID（L-VGCC-1D）在死后研究和啮齿动物模型中的作用。这些基因 显示不仅在接受PICRO急性或慢性输注的大鼠的HIPP中， BLn，但也在SZ和BD的HIPP中。这种在大鼠和大鼠之间的基因表达谱数据的重叠， 人体研究表明，该模型a）有效，B）获得的数据可靠，c）观察到的数据 可能与杏仁核-HIPP通路的激活有关， 环境压力除了上述靶基因外，我们还将研究亚基的表达 与NMDA（NR 2A），AMPA（GluR 1）和红藻氨酸（GluR 6）受体相关，因为许多死后 研究已经证明SZ中这些谷氨酸受体下调的证据， 兴奋性毒性与SZ和BD中的神经元功能障碍有关。选择的子单元显示 在慢性PICRO模型和精神病患者中表达降低。拟议 实验中，将使用慢性输注模式（PICRO连续输注4周）， 全身给予皮质酮（CORT）以模拟HIPP中可能发生的情况， 应对环境压力。我们将检验HIPP的杏仁核激活导致 GABA细胞的凋亡变化，通过谷氨酸受体和钙通道介导 活动