5-HT1A receptor anti-apoptotic transduction pathways in suicide

描述(申请人提供)：5-HT1a受体与焦虑、严重抑郁和自杀的病理有关。对突变小鼠的研究表明，5-HT1a受体对于大脑网络的长期生存是必要的。初步研究表明，5-HT1a受体下游信号分子的激活在自杀者的枕叶皮质(OC)中减弱。我们将通过比较伴重度抑郁症(MDD)的自杀者与伴精神分裂症(SZ)的自杀者以及非精神性、非自杀对照，来确定这种信号转导通路的减弱是重度抑郁症的特征还是与自杀素质有关。我们将评估四个大脑区域，其中一个区域我们发现主要抑郁和自杀都发生了变化(腹侧前额叶皮质，vPFC)，以及三个区域(前扣带回皮质[ACC]、背外侧PFC[BA9]和海马体)。我们预测与自杀相关的信号转导效应将出现在两个自杀组中，并局限于vPFC。我们预测与MDD相关的信号转导变化将在MDD自杀组而不是其他两组以及在ACC和背侧前额叶皮质中发现。我们将测试这一假设，即与细胞存活相关的5-HT1A受体激活的转导通路在与严重抑郁或自杀相关的特定大脑区域下调。我们将测量5-HT1A受体下游的信号蛋白，这些蛋白通过偶联到Gi/o和G亚基来调节。其中一个途径涉及GAI介导的对腺苷酸环化酶(AC)和蛋白激酶A(PKA)的抑制。5-羟色胺依赖的AC抑制通常被伴随的细胞生存通路的激活所抵消。我们认为，自杀中AC抑制的减少代表了一种机制，以抵消通过GBG亚单位激活的信号转导通路活性的降低。研究5-HT1a受体NFkB、PI3-K/Akt和ERKs在自杀中的激活将有助于我们进一步了解5-HT1a受体信号通路在抑郁和自杀行为中的作用。小脑半球将作为一个控制区。我们还将测量神经元密度、促凋亡信号分子和死亡效应分子的水平。我们假设，表达5-HT1a受体的脑细胞的活性或功能在严重抑郁或自杀时是神经危险的。从生物化学的角度解开这些事件，将对抑郁症和自杀的神经生物学产生至关重要的见解，这两个问题是美国和世界上的主要精神健康问题。它还可能确定治疗抑郁症和防止自杀的新药物靶点。公共卫生相关性：自杀行为是美国和世界的一个主要健康问题。在美国，每年有3万人死于自杀，自杀是第11大死因。我们有数据表明，与5-羟色胺1A受体相关的神经保护细胞通路在自杀时发生了改变。我们希望通过研究自杀者(抑郁症和精神分裂症患者)和正常对照的不同大脑区域中的这些通路来进一步探索这一点。我们希望深入了解自杀与抑郁症之间的神经生物学关系，并确定治疗抑郁症和预防自杀的新药物靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.