5-HT1A receptor anti-apoptotic transduction pathways in suicide

5-HT1A受体与焦虑、抑郁和自杀的病理学有关。外贸 突变小鼠的研究表明，5-HT1A受体是大脑网络长期生存所必需的。 初步研究表明，5-HT1A受体下游信号分子的激活是 在自杀者的枕叶皮层（OC）中减弱。我们将确定这种信号衰减 转导途径是重性抑郁症的特征，或与自杀素质有关， 比较重度抑郁症（MDD）自杀者与精神分裂症（SZ）自杀者和非精神病自杀者， 非自杀对照。我们将评估四个大脑区域，其中一个区域我们发现了两个主要的变化 抑郁症和自杀（腹侧前额叶皮层，vPFC）和三个区域，其中发现似乎更多 与重度抑郁症（前扣带皮层[ACC]，背外侧PFC [BA9]和 海马）。我们预测自杀相关的信号转导效应将存在于两个自杀组中 并局限于前额叶皮层我们推测MDD相关的信号转导改变可能存在于 抑郁症自杀组而非其他两组以及ACC和背侧前额叶皮层。我们将测试 与细胞存活相关的5-HT1A受体激活的转导途径被下调的假设 与重度抑郁症或自杀相关的特定大脑区域。我们将测量信号蛋白 5-HT1A受体的下游，其通过与Gi/o和G亚基偶联来调节。一种途径 涉及Gai介导的腺苷酸环化酶（AC）和蛋白激酶A（PKA）的抑制。5-HT依赖性 AC的抑制通常被伴随的细胞存活途径的激活所抵消。我们 我认为，自杀者中AC抑制作用的降低代表了一种抵消AC抑制作用降低的机制。 通过Gbg亚基激活的转导途径的活性。研究5-HT1A受体激活 NFkB、PI3-K/Akt和ERK在自杀中的相互作用将进一步加深我们对5-HT 1A受体信号作用的理解 抑郁和自杀行为的途径。小脑半球将作为控制区域。我们 还将测量神经元密度、促凋亡信号分子和死亡效应物的水平。我们 假设表达5-HT1A受体的脑细胞的活力或功能是 严重抑郁症或自杀的神经危险。从生物化学的角度来解释这些事件 深入了解抑郁症和自杀的神经生物学，美国和美国的主要心理健康问题， 世界它还可以确定治疗抑郁症和预防自杀的新药物靶点。自杀行为是美国和世界的一个主要健康问题。有3万人死于自杀 在美国，自杀是每年第11大死亡原因。我们有数据表明， 与5-羟色胺1A受体相关的细胞通路在自杀中被改变。我们想探索一下 通过进一步研究自杀者（抑郁症和精神分裂症）大脑不同区域的这些通路， 正常对照者我们希望深入了解自杀与抑郁的神经生物学，并确定新的 治疗抑郁症和预防自杀的药物靶点。

The 5-HT1A receptor is implicated in the pathology of anxiety, major depression and suicide. Studies with mutant mice indicate that the 5-HT1A receptor is necessary for the long-term viability of brain networks. Preliminary studies suggest that the activation of signaling molecules downstream of the 5-HT1A receptor is attenuated in the occipital cortex (OC) of suicides. We will determine whether this attenuation of signal transduction pathways is a characteristic of major depression or related to the diathesis for suicide by comparing suicides with major depression (MDD) to suicides with schizophrenia (SZ) and to nonpsychiatric, nonsuicide controls. We will evaluate four brain regions, one where we have found changes in both major depression and suicide (ventral prefrontal cortex, vPFC) and three regions where the findings seem more specifically linked to major depression (anterior cingulate cortex [ACC], dorsolateral PFC [BA9] and hippocampus). We predict signal transduction effects related to suicide will be present in both suicide groups and confined to the vPFC. We would predict the signal transduction changes related to MDD will be found in the MDD suicide group and not the other two groups and in the ACC and dorsal prefrontal cortex. We will test the hypothesis that 5-HT1A receptor-activated transduction pathways linked to cell survival are downregulated in specific brain regions relevant to major depression or for suicide. We will measure signaling proteins downstream of 5-HT1A receptors that are regulated via coupling to Gi/o and Gsubunits. One pathway involves the Gai-mediated inhibition of adenylyl cyclase (AC) and protein kinase A (PKA). The 5-HT-dependent inhibition of AC is normally counterbalanced by the concomitant activation of cell survival pathways. We propose that the reduced inhibition of AC in suicides represents a mechanism to counteract the reduction in the activity of the transduction pathways activated via the Gbg subunit. Investigating 5-HT1A receptor activation of NFkB, PI3-K/Akt and ERKs in suicide will advance our understanding of the role of 5-HT1A receptor signal pathways in depression and suicidal behavior. The cerebellar hemisphere will serve as a control region. We will also measure neuronal density, the levels of pro-apoptotic signaling molecules and death effectors. We hypothesize that the viability or functionality of brain cells that express 5-HT1A receptors is ¿neuroendangered¿ in major depression or suicide. Unraveling these events biochemically will yield crucial insights into the neurobiology of depression and suicide, major mental health problems in the US and the world. It may also identify novel drug targets for the treatment of depression and for the prevention of suicide. Suicidal behavior is a major health problem in the United States and the world. With 30,000 deaths by suicide per year in the US, suicide is the 11th leading cause of death. We have data indicating that the neuroprotective cellular pathways associated with the serotonin 1A receptor are altered in suicide. We want to explore this further by studying these pathways in various brain regions of suicides (depressed and schizophrenic) and normal controls. We hope to gain insight into the neurobiology of suicide versus depression and identify novel drug targets for treatment of depression and prevention of suicide.