Leptin regulation of GABAergic synaptogenesis and excitation-inhibition balance during development: effects of maternal obesity

瘦素对发育过程中 GABA 能突触发生和兴奋-抑制平衡的调节：母亲肥胖的影响

• 批准号: 10197984
• 负责人: Gary Allen Wayman
• 金额: $ 39.87万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197984
• 关键词: Address; Adult; Affect; Anxiety; Behavior; Behavioral; Biochemical; Brain; Brain region; Child; Chlorides; Cognition Disorders; Cognitive; Critical Pathways; Data; Development; Disease; Eating; Electrophysiology (science); Emotional; Emotional disorder; Epilepsy; Equilibrium; Food Energy; GABA Receptor; Goals; Hippocampus (Brain); Homeostasis; Human; Image; Immunologics; Impaired cognition; Knowledge; Leptin; Leptin deficiency; Life; Link; Long-Term Effects; Maintenance; Measures; Membrane; Mental Depression; Mental disorders; Metabolic Diseases; Methodology; Methods; Mission; Molecular; Moods; Neurons; Obesity; Pathogenesis; Pathologic; Pathway interactions; Play; Pregnancy; Prevention approach; Process; Public Health; Regulation; Research; Rett Syndrome; Risk; Schizophrenia; Signal Transduction; Signal Transduction Pathway; Synapses; Synaptic plasticity; Testing; United States National Institutes of Health; autism spectrum disorder; autistic behaviour; behavioral impairment; cognitive function; critical developmental period; critical period; developmental disease; early onset; gamma-Aminobutyric Acid; in vivo; innovation; maternal obesity; nervous system disorder; neuron development; neuropsychiatric disorder; neurotrophic factor; neurotropic; novel; obesity treatment; painful neuropathy; receptor; receptor expression; synaptic function; synaptogenesis; trafficking

Leptin is a critical neurotrophic factor during development. Its receptors (LepRs) are found throughout the brain, including in the hippocampus. Leptin deficiency is also associated with cognitive and emotional impairment, behaviors impacted by hippocampal function. Intriguingly, leptin levels rise during a critical developmental period when hippocampal synaptogenesis is occurring. We have demonstrated that leptin induces GABAergic synaptogenesis and controls Cl- homeostasis to promote an excitatory effect of GABA during this critical period. In contrast, a lack of leptin shifts the excitation/inhibition balance so that GABA is more inhibitory, and reduces GABAergic synaptogenesis. Excessive leptin during development (hyperleptinemia) prolongs the excitatory action of GABA and increases GABA receptor expression, suggesting that it may have long-term effects on hippocampal function. Intriguingly, leptin levels are elevated in children with early onset autism spectrum disorders (ASD) and Rett syndrome, a disease showing “autistic-like” behaviors. Maternal obesity, which affects 1 in 5 pregnancies, is also associated with hyperleptinemia in humans, and also heightens the risk of ASD and other neuropsychiatric disorders in children. One potential mechanism by which maternal obesity, and the associated hyperleptinemia, could impact the likelihood of a child or an adult developing emotional and cognitive disorders is through alterations in the development, maintenance, function or plasticity of GABAergic connections. However, the effects of hyperleptinemia and maternal obesity on the development and function of GABA synapses is not known. Understanding how maternal obesity alters the developmental effects of leptin and the formation of critical hippocampal synaptic connections in vivo is an essential first step to understanding the mechanisms by which maternal obesity impacts hippocampal function later in life. Our central hypothesis is that leptin plays a key role in regulating GABAergic synaptic development and plasticity and that pathological hyperleptinemia alters this process through changes in the expression and membrane localization of key components of GABAergic synapses and regulators of Cl- homeostasis. We will test our central hypothesis with three specific aims. 1) Determine how leptin alters Cl- homeostasis and stimulates GABAergic synaptogenesis in vivo 2) Determine whether developmental leptin impacts GABAergic synaptic function and plasticity. 3) Determine if maternal obesity and associated hyperleptinemia alters GABAergic synaptogenesis, Cl- homeostasis and GABAergic synaptic function and plasticity. While we have focused on the hippocampus, this knowledge is expected to have broad impact, as it should also be applicable to leptin-induced synapse formation in other brain regions, including pathways critical for the control of food intake and energy homeostasis. This research therefore should have implications for both mental health disorders, such as mood, cognitive disorders and metabolic disorders such as obesity.

瘦素是发育过程中关键的神经营养因素。它的接收器（LEPR）在整个过程中发现 大脑，包括海马。瘦素缺乏症也与认知和情感有关 受损，受海马功能影响的行为。有趣的是，瘦素水平在关键时期上升 海马突触发生的发育期。我们已经证明了瘦素 诱导GABA能突触发生并控制CL-稳态以促进GABA的兴奋作用 在这个关键时期。相比之下，缺乏瘦素会改变兴奋/抑制平衡，因此GABA是 更多的抑制作用，并减少GABA能突触发生。发育过程中过量的瘦素 （高勒普汀）延长GABA的兴奋作用，并增加GABA受体表达， 表明它可能会对海马功能产生长期影响。有趣的是，瘦素水平是 早期发作自闭症谱系障碍（ASD）和RETT综合征的儿童升高 显示“自闭症”行为。孕产妇肥胖影响5分之一的怀孕，也与 人类的高血治血症，还增加了ASD和其他神经精神疾病的风险 孩子们。物物肥胖和相关的高稀释血症的一种潜在机制可以 影响儿童或成人发展情绪和认知障碍的可能性是通过 加巴能连接的开发，维护，功能或可塑性的改变。但是， 高血治和孕产妇肥胖对GABA突触的发展和功能的影响不是 已知。了解产妇肥胖如何改变瘦素的发育效果和形成 体内关键海马突触连接是理解机制的重要第一步 孕产妇肥胖在以后的生活中影响海马功能。我们的中心假设是瘦素 在调节GABA能突触发展和可塑性方面起着关键作用，该病理学 高级血症通过改变键的表达和膜定位来改变这一过程 Cl-稳态的GABA能突触和调节剂的组成部分。我们将检验我们的中心假设 具有三个具体目标。 1）确定瘦素如何改变Cl-稳态并刺激GABA能 体内突触发生2）确定发育瘦素是否影响GABA能突触功能 和可塑性。 3）确定孕妇肥胖和相关的高稀释血症是否改变了Gabaergic 突触发生，CL-稳态和GABA能突触功能和可塑性。虽然我们专注于 在海马上，预计该知识将产生广泛的影响，因为它也应适用于 瘦素诱导的其他大脑区域的突触形成，包括控制食物至关重要的途径 摄入量和能量稳态。因此，这项研究应该对心理健康有影响 疾病，例如情绪，认知障碍和代谢障碍，例如肥胖症。