Suppression of inhibitory GABAergic transmission by cAMP signaling pathway: alterations in learning and memory mutants.
Suppression of inhibitory GABAergic transmission by cAMP signaling pathway: alterations in learning and memory mutants.
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DOI：
10.1111/ejn.12144
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Lee D
中科院分区：
文献类型：
--
作者：
Ganguly A;Lee D
cAMP 信号通路介导突触可塑性，对于脊椎动物和无脊椎动物的记忆形成至关重要。在果蝇果蝇中，cAMP 通路的突变会导致嗅觉学习受损。这些突变基因优先在蘑菇体（MB）中表达，蘑菇体是学习所必需的解剖结构。虽然已知 cAMP 介导的突触可塑性参与兴奋性突触的促进，但对其在 GABA 能突触可塑性和学习中的功能知之甚少。在这项研究中，我们利用全细胞膜片钳技术对果蝇原代神经元培养物进行研究，证明局部应用腺苷酸环化酶激活剂毛喉素 (FSK) 可抑制抑制性 GABA 能突触后电流 (IPSC)。我们观察到 FSK 对 GABA 能传递的双重调节作用，它增加 GABA 能突触的整体兴奋性，同时作用于突触后 GABA 受体以抑制 GABA 能 IPSC。此外，我们还发现 cAMP 通过突触后机制以 PKA 依赖性方式减少 GABA 能 IPSC。 PKA 通过调节离子型 GABA 受体对神经递质 GABA 的敏感性发挥作用。 GABA 能 IPSC 的这种调节在 cAMP 通路和短期记忆突变体 dunce 和芜菁甘蓝中发生改变，两者都表现出改变的 GABA 受体敏感性。有趣的是，这种效应在这两种突变体的 MB 神经元中也被保留。因此，我们的研究表明，cAMP 介导的 GABA 能可塑性的改变，特别是 cAMP 突变体的 MB 神经元中的改变，解释了它们的嗅觉学习缺陷。
The cAMP signaling pathway mediates synaptic plasticity and is essential for memory formation in both vertebrate and invertebrates. In the fruit fly Drosophila melanogaster, mutations in the cAMP pathway lead to impaired olfactory learning. These mutant genes are preferentially expressed in the mushroom body (MB), an anatomical structure essential for learning. While cAMP-mediated synaptic plasticity is known to be involved in facilitation at the excitatory synapses, little is known about its function in GABAergic synaptic plasticity and learning. In this study, using whole-cell patch clamp technique on Drosophila primary neuronal cultures, we demonstrate that focal application of an adenylate cyclase activator forskolin (FSK) suppresses inhibitory GABAergic postsynaptic currents (IPSCs). We observed a dual regulatory role of FSK on GABAergic transmission, where it increases overall excitability at GABAergic synapses, while simultaneously acting on postsynaptic GABA receptors to suppress GABAergic IPSCs. Further we show that cAMP decreases GABAergic IPSCs in a PKA-dependent manner through a postsynaptic mechanism. PKA acts through the modulation of ionotropic GABA receptor sensitivity to the neurotransmitter GABA. This regulation of GABAergic IPSCs is altered in the cAMP pathway and short-term memory mutants dunce and rutabaga, with both showing altered GABA receptor sensitivity. Interestingly, this effect is also conserved in the MB neurons of both these mutants. Thus, our study suggests that alterations of cAMP-mediated GABAergic plasticity, particularly in the MB neurons of cAMP mutants, account for their defects in olfactory learning.
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影响因子：
5.7
作者：
Castillo PE;Chiu CQ;Carroll RC
通讯作者：
Carroll RC
DOI：
10.1073/pnas.73.5.1684
发表时间：
1976-01-01
影响因子：
11.1
作者：
DUDAI, Y;JAN, YN;BENZER, S
通讯作者：
BENZER, S
影响因子：
64.8
作者：
BYERS, D;DAVIS, RL;KIGER, JA
通讯作者：
KIGER, JA
影响因子：
2.5
作者：
Floyer-Lea, A;Wylezinska, M;Matthews, PM
通讯作者：
Matthews, PM
影响因子：
16.2
作者：
Gervasi, Nicolas;Tchenio, Paul;Preat, Thomas
通讯作者：
Preat, Thomas