Impact of histamine H3 receptor agents on PAE-induced synaptic plasticity deficits in dentate gyrus

组胺 H3 受体药物对 PAE 诱导的齿状回突触可塑性缺陷的影响

• 批准号: 10207335
• 负责人: Daniel D. Savage
• 金额: $ 30.85万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207335
• 关键词: Address; Affect; Agonist; Back; Behavior; Behavior Therapy; Behavior assessment; Behavioral; Biological Assay; Biosensor; Brain; Chemosensitization; Clinical; Clinical Trials; Collaborations; Complement; Coupling; Diagnosis; Dose; Electrophysiology (science); Ethanol; Excitatory Postsynaptic Potentials; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Frequencies; GTP Binding; Glutamates; Goals; Histamine H3 Agonist; Histamine H3 Receptors; Histologic; In Situ Hybridization; In Vitro; Intervention; Learning; Learning Disabilities; Long-Term Potentiation; Measurement; Measures; Mediating; Memory; Modeling; Neurobiology; Neurons; Patients; Pharmaceutical Preparations; Phase; Physiologic pulse; Physiology; Probability; Problem behavior; Protein Isoforms; Quantitative Reverse Transcriptase PCR; Rattus; Reporting; Research; Reversal Learning; Slice; Synaptic Transmission; Synaptic plasticity; awake; base; dentate gyrus; differential expression; entorhinal cortex; extracellular; fetal; granule cell; in vivo; mRNA Expression; memory retention; neuroimaging; neurotransmission; novel; offspring; pre-clinical; response; synaptic inhibition; touchscreen

PROJECT SUMMARY Learning disabilities are the most common behavioral deficit observed in patients with Fetal Alcohol Spectrum Disorder (FASD). Currently, there are no established clinically effective pharmacotherapeutic interventions for these behavioral problems. Using a well-established rat model of FASD, we have reported that the histamine H3 receptor inverse agonist / antagonist ABT-239 ameliorates prenatal alcohol exposure (PAE)-induced deficits in synaptic plasticity and learning. We have also observed increased H3 receptor-effector coupling and a heightened H3 receptor-mediated inhibition of the probability of glutamate release in dentate gyrus of PAE rats. Collectively, these results suggest that PAE increases H3 receptor-mediated inhibition of glutamate release and that ABT-239 reduces this heightened inhibitory influence. One parsimonious explanation for why PAE rats are more sensitive to H3 receptor agents is a PAE-induced increase in the expression of the rH3A isoform of histamine H3 receptors relative to the rH3C isoform. This putative shift would confer greater sensitivity to the inhibitory effects of histamine H3 receptor agonists in PAE rats. The principal objectives of this NMARC research component application are to: 1) Examine whether PAE increases the expression of rH3A relative to rH3C in entorhinal cortical neurons projecting to the dentate gyrus. 2) More thoroughly establish the consequences of a PAE-induced elevation in H3 receptor-effector coupling and the effects of second H3 receptor inverse agonist / antagonist namely, SAR152954, on H3 receptor-mediated inhibition of glutamatergic neurotransmission in dentate gyrus. In Specific Aim 1A, we will employ in situ hybridization and qRT-PCR approaches to first confirm whether PAE increases the rH3A/rH3C mRNA expression ratio. In Aim 1B, we will use a [35S]-GTPS binding assay in histological sections to conduct a more detailed examination of the effects of PAE on H3 receptor- effector coupling and assess the differential sensitivity of PAE rats to SAR152954 relative to controls. In Specific Aim 2A, we will conduct in vitro slice physiology studies to examine: 1) The impact of PAE on the effects of the H3 receptor agonist methimepip on fEPSP responses and pair-pulse plasticity in dentate gyrus, under baseline and after theta burst stimulation conditions. 2) The effects of SAR152954 alone and in the presence of methimepip on paired-pulse ratio and long-term potentiation. In Aim 2B, we will examine the impact of PAE on fEPSP and PPR before and after high frequency stimulations in awake freely moving rats. We predict that SAR152954 will ameliorate the heightened H3 receptor mediated inhibition of synaptic plasticity in PAE rats at concentrations/doses that do not impair synaptic transmission in control rats. These studies address two of the three strategic objectives of NMARC, namely advancing our understanding of the neurobiological consequences of PAE, as well as working towards establishing the mechanistic basis for novel interventions to treat of PAE- induced deficits in synaptic plasticity and memory. These studies could provide additional preclinical rational for considering drugs such as SAR152954 for clinical trials in patients with FASD. 1

项目摘要 学习障碍是在胎儿酒精谱系患者中观察到的最常见的行为防御 障碍（FASD）。目前，尚无针对临床有效的药物治疗干预措施 这些行为问题。使用良好的FASD大鼠模型，我们报告了组胺 H3受体反向激动剂 /拮抗剂ABT-239改善产前酒精暴露（PAE）诱导的缺陷 在突触可塑性和学习中。我们还观察到H3受体效应器偶联和A H3受体介导的PAE大鼠齿状回中谷氨酸释放概率的抑制作用。 总的来说，这些结果表明，PAE增加了H3受体介导的对谷氨酸释放的抑制作用，并且 ABT-239降低了这种抑制作用的增强。一个简约的解释，为什么Pae老鼠是 对H3受体剂更敏感的是PAE诱导的RH3A同工型表达的增加 组胺H3受体相对于RH3C同工型。这种推定的转变将使对 组胺H3受体激动剂在PAE大鼠中的抑制作用。这项NMARC研究的主要目标 组件应用是：1）检查PAE是否会增加RH3A相对于RH3C的表达 投射到齿状回的内嗅皮质神经元。 2）更彻底地确定 PAE诱导的H3受体效应器偶联的升高以及第二H3受体反向激动剂 /的影响 拮抗剂，即SAR152954，在H3受体介导的谷氨酸能神经传递的抑制 齿状回。在特定的目标1a中，我们将采用原位杂交和QRT-PCR方法首先确认 PAE是否增加RH3A/RH3C mRNA表达比。在AIM 1B中，我们将使用[35s]-gtps绑定 在组织学部分中的测定，对PAE对H3受体的影响进行更详细的检查 效应子耦合并评估PAE大鼠对SAR152954相对于对照的差异敏感性。具体 AIM 2A，我们将进行体外切片生理研究以检查：1）PAE对 H3受体激动剂MethimePIP在基线下的FEPSP响应和齿状回的成对脉冲可塑性上 并在theta爆发刺激条件下。 2）单独使用SAR152954的影响 Methimepip对配对脉冲比和长期潜在的甲板。在AIM 2B中，我们将研究PAE对 FEPSP和PPR在醒着的自由移动大鼠中高频刺激前后。我们预测 SAR152954将改善增强的H3受体介导的PAE大鼠突触可塑性的抑制作用 不会损害控制大鼠合成传播的浓度/剂量。这些研究涉及两个 NMARC的三个战略目标，即促进我们对神经生物学后果的理解 PAE，并致力于建立新的干预措施的机械基础，以治疗Pae- 引起突触可塑性和记忆力的缺陷。这些研究可以为 考虑使用FASD患者的临床试验的SAR152954等药物。 1