Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus.
Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus.
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DOI：
10.3389/fncel.2014.00235
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发表时间：
2014
影响因子：
5.3
通讯作者：
Gaiarsa JL
中科院分区：
文献类型：
--
作者：
Guimond D;Diabira D;Porcher C;Bader F;Ferrand N;Zhu M;Appleyard SM;Wayman GA;Gaiarsa JL
越来越清楚的是，瘦素不仅是一种调节能量稳态的激素，而且还是一种神经营养因子，影响着包括海马体在内的许多大脑区域。虽然瘦素促进下丘脑GABA能传递的发展，但对其在海马区GABA能系统中的作用知之甚少。在这里，我们展示了瘦素调节GABA能传递到发育中的新生大鼠CA3锥体细胞。具体地说，瘦素诱导微小GABAA受体介导的突触后电流(GABAA-PSC)频率的长持续增强(LLP-GABAA)。瘦素还增加了部分神经元中诱发的GABAA-PSCs的幅度，同时变异系数降低，成对脉冲比率没有变化，表明功能性突触的招募增加。在记录吸管中加入药物阻滞剂表明，瘦素诱导的LLP-GABAA需要从内库释放的突触后钙，以及突触后MAPK/ERK激酶1和/或2(MEK1/2)、磷脂酰肌醇3激酶(PI3K)和钙-钙调蛋白激酶(CaMKK)。最后，对瘦素缺乏的ob/ob小鼠的CA3锥体细胞的研究显示，与野生型相比，微型GABAA-PSCs的基本频率降低。此外，突触前GAD65免疫染色在突变动物的CA3层锥体中减少，这两个结果都表明ob/ob小鼠中功能性GABA能突触的数量减少。总之，这些结果表明，瘦素可能通过增加功能性突触的数量来增强和促进发育中的海马区GABA能突触传递的发展，并为调节这一效应的细胞内途径提供了洞察力。本研究进一步将瘦素的神经营养作用范围扩展到海马区发育和功能的关键调节因子，即GABA能传递。
It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA) of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC) frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2), phosphoinositide 3 kinase (PI3K) and calcium-calmodulin kinase kinase (CaMKK). Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin's neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission.
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