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.

瘦素是发育过程中重要的神经营养因子。它的受体（lepr）遍布整个大脑