Latrophilin-3 and ADHD: A new potential mechanism

Latrophilin-3 和 ADHD：一种新的潜在机制

• 批准号: 8566031
• 负责人: Charles V Vorhees
• 金额: $ 19.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566031
• 关键词: Acoustics; Affect; Animals; Attention; Attention deficit hyperactivity disorder; Behavioral; Binding; Brain; Centers for Disease Control and Prevention (U.S.); Child; Cognitive; Data; Densitometry; Development; Disease; Dopamine; Dopamine-beta-monooxygenase; Effectiveness; Ensure; Etiology; Future; Genes; Glutamates; Hyperactive behavior; Immunohistochemistry; Impulsivity; Knock-out; Modeling; Motor Activity; Mutation; N-Methylaspartate; NR1 gene; Norepinephrine; Orphan; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Prevalence; Process; Proteins; Rattus; Reaction Time; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Serotonin; Severities; Short-Term Memory; Signal Transduction; Staining method; Stains; Symptoms; System; Testing; Therapeutic Intervention; Tyrosine 3-Monooxygenase; Western Blotting; alpha-latrotoxin receptor; base; behavior test; boys; cost; drug development; flexibility; follow-up; gamma-Aminobutyric Acid; girls; high risk; improved; inattention; innovation; insight; interest; loss of function; monoamine; neurochemistry; novel; performance tests; prepulse inhibition; public health relevance; receptor; research study; response; reuptake

DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) affects 5.4 million children at a cost >$72 billion/year, yet its etiology is poorly understood. A new gene for an orphan receptor has been identified that conveys high risk for ADHD: Latrophilin-3 (LPHN3). We have a new Lphn3 knock-out (KO) rat. This rat shows hyperactivity and hyper-reactivity. But ADHD also affects attention and impulse control. Objective-1 will test Lphn3 KO rats for attention and inhibitory control. ADHD is treated with stimulants, which increase attention and reduce distractibility and activity. Objective-2 is to test the effects of ADHD medications in Lphn3 KO rats. Effective ADHD medications increase dopamine and norepinephrine signaling (and some increase 5HT) by acting on monoamine reuptake and release processes or receptors. Objective-3 is to determine the effects of Lphn3 disruption on monoamines, transporters, and receptors. The overall purpose is to identify the contribution of Lphn3 to the behavioral and neurochemical phenotype of ADHD. The proposed experiments will generate essential data for how Lphn3 contributes to each of the symptoms and neurochemical changes associated with ADHD. Lphn3 could become a novel target for development of drugs that modulate Lphn3 function or its binding partner (Flrt3) to alleviate the underlying deficit in ADHD. As such this represents innovative research on a cause of ADHD. We are the only group with the Lphn3 KO rat and pilot phenotypic data. Therefore, we are uniquely position to pursue this model. Specific Aim-1 will determine the ADHD-like phenotype of Lphn3 KO rats. The role of Lphn3 loss of function in extended locomotor activity, sensorimotor gating, cognitive flexibility/attention (set shifting), attention/flexibility (continuous performance test), working memory, and response to ADHD medications will be assessed. The data will demonstrate the range and severity of ADHD phenotype. Specific Aim-2 will elucidate the neurochemical changes in Lphn3 KO rats. Exp-2a: KO and WT rats will be compared by immunohistochemistry for changes in monoamines implicated in ADHD (dopamine (by tyrosine hydroxylase), 5HT, and dopamine beta hydroxylase (for NE), and as controls GAD67 (for GABA) and NMDA-NR1 (for glutamate). Stains for each transporter will be performed. Because the dopamine D4 and 5HT2B receptors have been implicated in ADHD they will also be assessed. Exp-2b: Once histological regions of change are identified, other animals will have these regions analyzed by Western blot. Exp-2c: Once Westerns from Aim-2b identify significant changes, this will be used to guide which markers will be analyzed in Aim-2c in animals after behavioral testing; then correlations between neurochemical and behavioral data will be performed. In addition, RT-PCR for Flrt3 will be performed to determine it is altered by the Lphn3 mutation. These experiments will materially advance the field of ADHD research.

描述（由申请人提供）：注意力缺陷多动症（ADHD）以每年720亿美元的损失影响540万儿童，但其病因却鲜为人知。已经确定了一个新的孤儿受体基因，它传达了ADHD的高风险：Latrophilin-3（LPHN3）。我们有一个新的LPHN3淘汰赛（KO）老鼠。该大鼠表现出多动症和过度反应性。但是ADHD也会影响注意力和冲动控制。 Objective-1将测试LPHN3 KO大鼠的注意力和抑制性控制。 ADHD用兴奋剂治疗，从而增加注意力并降低分心和活性。 Objective-2是测试ADHD药物在LPHN3 KO大鼠中的影响。有效的多动症药物通过作用于单胺再摄取和释放过程或受体来增加多巴胺和去甲肾上腺素信号传导（有些增加5HT）。 Objective-3是确定LPHN3破坏对单胺，转运蛋白和受体的影响。总体目的是确定LPHN3对ADHD的行为和神经化学表型的贡献。提出的实验将生成LPHN3如何促进与ADHD相关的每种症状和神经化学变化的基本数据。 LPHN3可能成为调节LPHN3功能或其结合伴侣（FLRT3）的药物开发的新目标，以减轻ADHD中的潜在赤字。因此，这代表了有关多动症原因的创新研究。我们是唯一具有LPHN3 KO大鼠和试验表型数据的组。因此，我们是追求这一模型的独特位置。特定的AIM-1将确定LPHN3 KO大鼠的ADHD样表型。 LPHN3功能在扩展运动活性，感觉运动门控，认知灵活性/注意力（​​设置转移），注意/灵活性（连续性能测试），工作记忆以及对ADHD药物的反应中的作用。数据将证明ADHD表型的范围和严重程度。特定的AIM-2将阐明LPHN3 KO大鼠的神经化学变化。 Exp-2a: KO and WT rats will be compared by immunohistochemistry for changes in monoamines implicated in ADHD (dopamine (by tyrosine hydroxylase), 5HT, and dopamine beta hydroxylase (for NE), and as controls GAD67 (for GABA) and NMDA-NR1 (for glutamate). Stains for each transporter will be performed. Because多巴胺D4和5HT2B受体与ADHD有关，也将评估Exp-2b：一旦确定了其他动物的组织学区域。进行。此外，将进行FLRT3的RT-PCR，以确定LPHN3突变的改变。