Noradrenergic modulation of electrical coupling in GABAergic networks of the hippocampus
Noradrenergic modulation of electrical coupling in GABAergic networks of the hippocampus
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DOI：
10.1523/jneurosci.4616-07.2008
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发表时间：
2008-02-20
影响因子：
5.3
通讯作者：
Maccaferri, Gianmaria
中科院分区：
文献类型：
--
作者：
Zsiros, Veronika;Maccaferri, Gianmaria
去甲肾上腺素能调节皮质环路参与信息处理、高级功能的调节和癫痫活动的预防。在这里，我们研究了去甲肾上腺素对海马GABA能网络功能连通性的影响，并表明中间神经元之间的电突触是去甲肾上腺素能体外调节的新靶点。应用去甲肾上腺素或选择性的β-肾上腺素能激动剂异丙肾上腺素，可使陷窝-分子间神经元配对记录中基于缝隙连接的偶联减少约40%。用Forsklin对腺酰环化酶进行药物刺激后，也得到了类似的结果。相反，腺酰环化酶拮抗剂MDL12330A[顺式-N-(2-苯基环戊基)氮杂环三酮-1-烯-2-胺]或特异性蛋白激酶A抑制剂H89(N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide二盐酸盐使偶联的基础强度增加了约30%。此外，PKA介导的磷酸化对异丙肾上腺素和Forsklin依赖的偶联调节都是关键的，因为在记录管中加入PKA拮抗剂KT5720[(9S，10R，12R)-2，3，9，10，11，12-六氢-10-hydroxy-9-methyl-1-oxo-9，12-epoxy-1H-diindolo[1，2，3-fg:3‘，2’，1‘-KL]吡咯[3，4-I][1，6]苯并重氮-10-羧酸己酯]可以阻止调节。最后，我们研究了β-肾上腺素能调制对GABA能网络内混合多突触传递的影响。异丙肾上腺素抑制GABA(A)受体介导的突触电流的传播，但不显著改变GABA能直接输入，表明电耦合的调节增加了化学突触产生的信息流的灵活性。综上所述，GABA能神经网络中β-肾上腺素能受体的激活通过cAMP/PKA信号级联减少了突触的电传递，并影响了突触在回路内的分化程度。我们认为，GABA能网络中电和化学突触传递之间的这种动态调制和相互作用有助于体内记忆过程的调节，并防止超同步活动。
Noradrenergic modulation of cortical circuits is involved in information processing, regulation of higher functions, and prevention of epileptic activity. Here, we studied the effects of noradrenaline on the functional connectivity of GABAergic networks of the hippocampus and show that electrical synapses between interneurons are a novel target of noradrenergic modulation in vitro. Application of noradrenaline or of the selective beta-adrenergic agonist isoproterenol decreased gap junction-based coupling in paired recordings from stratum lacunosum-moleculare interneurons by similar to 40%. Similar results were obtained after pharmacological stimulation of the adenylyl cyclase with forskolin. In contrast, the adenylyl cyclase antagonist MDL 12330A[cis-N-(2-phenylcyclopentyl) azacyclotridec-1-en-2-amine] or the specific protein kinase A (PKA) inhibitor H89 (N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride) enhanced the basal strength of coupling by similar to 30%. In addition, PKA-mediated phosphorylation was critical for both isoproterenol- and forskolin-dependent regulation of coupling, because inclusion of the PKA antagonist KT5720 [(9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10- hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3 ',2 ',1 '-kl] pyrrolo[3,4- i][1,6]benzodiazocine-10-carboxylicacid hexyl ester] in the recording pipettes prevented modulation.Lastly, we studied the effects of beta-adrenergic modulation on mixed polysynaptic transmission within the GABAergic network. Isoproterenol depressed propagation of GABA(A) receptor-mediated synaptic currents, but did not change significantly direct GABAergic input, indicating that regulation of electrical coupling adds flexibility to the information flow generated by chemical synapses. In conclusion, activation of beta-adrenergic receptors in stratum lacunosum-moleculare GABAergic networks reduces electrical synaptic transmission via a cAMP/PKA signaling cascade, and affects the degree of synaptic divergence within the circuit. We propose that this dynamic modulation and interplay between electrical and chemical synaptic transmission in GABAergic networks contributes to the tuning of memory processes in vivo, and prevents hypersynchronous activity.