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

瘦素是一种重要的神经营养因子。它的受体（LepRs）在整个 大脑，包括海马。瘦素缺乏也与认知和情绪有关 海马功能影响的行为。有趣的是，瘦素水平在关键时期会上升 海马突触发生的发育时期。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，缺乏瘦素改变了兴奋/抑制平衡，使得GABA被激活。 抑制性更强，并减少GABA能突触发生。发育期瘦素过多 （高瘦素血症）抑制GABA的兴奋作用并增加GABA受体表达， 这表明它可能对海马功能产生长期影响。有趣的是，瘦素水平 在患有早发性自闭症谱系障碍（ASD）和Rett综合征（一种疾病 表现出“类似自闭症”的行为孕妇肥胖，影响五分之一的怀孕，也与 高瘦素血症，也增加了ASD和其他神经精神疾病的风险， 孩子一种可能的机制是母亲肥胖和相关的高瘦素血症， 影响儿童或成人发展情感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。但 高瘦素血症和母亲肥胖对GABA突触的发育和功能的影响不是 知道的了解母体肥胖如何改变瘦素的发育效应和肥胖的形成 关键的海马体突触连接在体内是了解机制的重要的第一步 母亲肥胖会影响日后海马体的功能。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关键蛋白的表达和膜定位来改变这一过程。 GABA能突触的组分和Cl-稳态的调节剂。我们将检验我们的中心假设 有三个具体目标。1)确定瘦素如何改变Cl-稳态并刺激GABA能 2）确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改变GABA能 突触发生、Cl-稳态和GABA能突触功能和可塑性。当我们专注于 在海马体上，这一知识预计将产生广泛的影响，因为它也应该适用于 瘦素诱导其他大脑区域的突触形成，包括对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和 这些疾病包括情绪障碍、认知障碍和代谢障碍如肥胖症。

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.