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: 10436314
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436314
• 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.

瘦素是发育过程中一种重要的神经营养因子。其受体(LepRs)广泛分布于 大脑，包括在海马体中。瘦素缺乏也与认知和情绪有关 损害，受海马体功能影响的行为。有趣的是，瘦素水平在关键时期会上升 海马区突触发生的发育期。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。相反，缺乏瘦素会改变兴奋/抑制平衡，从而使GABA 更多的抑制，并减少GABA能突触发生。发育过程中的过量瘦素 (高瘦素血症)延长GABA的兴奋作用，增加GABA受体的表达， 这表明它可能对海马体功能有长期影响。有趣的是，瘦素水平 早发性自闭症谱系障碍(ASD)和Rett综合征儿童的升高 表现出“自闭症样”的行为。母体肥胖影响着五分之一的孕妇，也与 人类的高瘦素血症，也增加了ASD和其他神经精神疾病的风险 孩子们。母体肥胖和相关的高瘦素血症的一个潜在机制可能 影响儿童或成人发展情绪和认知障碍的可能性是通过 GABA能连接的发育、维持、功能或可塑性的改变。然而， 高瘦素血症和母体肥胖对GABA突触发育和功能的影响 为人所知。了解母亲肥胖如何改变瘦素的发育效应和瘦素的形成 体内关键的海马区突触连接是了解其机制的重要第一步 母体肥胖对晚年海马体功能的影响。我们的中心假设是瘦素 在调节GABA能突触发育和可塑性中起关键作用 高瘦素血症通过改变KEY的表达和膜定位来改变这一过程 GABA能突触的组成和氯离子稳态的调节。我们将检验我们的中心假设 有三个明确的目标。1)确定瘦素如何改变氯稳态和刺激GABA能 体内突触发生2)决定发育中的瘦素是否影响GABA能突触功能 和可塑性。3)确定母亲肥胖和相关的高瘦素血症是否会改变GABA 突触发生、氯离子稳态与GABA能突触功能和可塑性。当我们专注于 在海马体上，这一知识预计会产生广泛的影响，因为它也应该适用于 瘦素诱导大脑其他区域的突触形成，包括控制食物的关键通路 摄入量和能量平衡。因此，这项研究应该对两个人的心理健康都有影响 障碍，如情绪、认知障碍和代谢障碍，如肥胖。

项目成果

Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities.

人类 BDNF/TrkB 变异会损害海马突触发生并与神经行为异常相关。

• DOI: 10.1038/s41598-020-65531-x
• 发表时间: 2020
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Sonoyama,Takuhiro;Stadler,LukasKJ;Zhu,Mingyan;Keogh,JuliaM;Henning,Elana;Hisama,Fuki;Kirwan,Peter;Jura,Magdalena;Blaszczyk,BeataK;DeWitt,DavidC;Brouwers,Bas;Hyvönen,Marko;Barroso,Inês;Merkle,FlorianT;Appleyard,SuzanneM

Tropomodulin's Actin-Binding Abilities Are Required to Modulate Dendrite Development.

• DOI: 10.3389/fnmol.2018.00357
• 发表时间: 2018
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Gray KT;Stefen H;Ly TNA;Keller CJ;Colpan M;Wayman GA;Pate E;Fath T;Kostyukova AS
• 通讯作者: Kostyukova AS

Leptin stimulates synaptogenesis in hippocampal neurons via KLF4 and SOCS3 inhibition of STAT3 signaling.

• DOI: 10.1016/j.mcn.2020.103500
• 发表时间: 2020-07
• 期刊: Molecular and cellular neurosciences
• 作者: Sahin GS;Dhar M;Dillon C;Zhu M;Shiina H;Winters BD;Lambert TJ;Impey S;Appleyard SM;Wayman GA
• 通讯作者: Wayman GA

Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal neurons.

• DOI: 10.1126/scisignal.abe4111
• 发表时间: 2021-05-18
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Sahin GS;Luis Rodriguez-Llamas J;Dillon C;Medina I;Appleyard SM;Gaiarsa JL;Wayman GA
• 通讯作者: Wayman GA

The adipocyte hormone leptin sets the emergence of hippocampal inhibition in mice.

• DOI: 10.7554/elife.36726
• 发表时间: 2018-08-14
• 期刊: eLife
• 影响因子: 7.7
• 作者: Dumon C;Diabira D;Chudotvorova I;Bader F;Sahin S;Zhang J;Porcher C;Wayman G;Medina I;Gaiarsa JL
• 通讯作者: Gaiarsa JL