Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons
Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons
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DOI：
10.1523/jneurosci.21-10-03628.2001
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发表时间：
2001-05-15
影响因子：
5.3
通讯作者：
Yang, CR
中科院分区：
文献类型：
--
作者：
Seamans, JK;Gorelova, N;Yang, CR
多巴胺调节前额叶皮层中处理工作记忆信息的神经网络的活动，但人们对其精确的生物物理作用知之甚少。本研究采用离体全细胞膜片钳技术观察了多巴胺对前额叶锥体神经元GABA能输入的影响。在大多数锥体细胞中，多巴胺对诱发的IPSC具有时间双相效应，产生初始振幅突然降低，随后延迟IPSC振幅增加。使用受体亚型特异性激动剂和拮抗剂，我们发现最初的突然减少是D2受体介导的，而后期，缓慢发展的增强是D1受体介导的。线性结合两种激动剂的作用可以重现双相多巴胺效应。由于D1激动剂增强自发性（sIPSC），但不影响微型（mIPSC）IPSC，似乎D1激动剂通过增加中间神经元及其轴突的内在兴奋性引起更大的诱发IPSC。相反，D2激动剂对sIPSC没有影响，但确实使mIPSC显著减少，表明GABA释放概率降低。此外，D2激动剂减少了对GABA（A）激动剂的突触后反应。因此，D1和D2受体以相反的方式和通过不同的机制调节前额叶皮层（PFC）锥体细胞中的GABA能活性。这种双向调制可能对有源PFC网络的计算特性产生重要影响。
Dopamine regulates the activity of neural networks in the prefrontal cortex that process working memory information, but its precise biophysical actions are poorly understood. The present study characterized the effects of dopamine on GABAergic inputs to prefrontal pyramidal neurons using whole- cell patch-clamp recordings in vitro. In most pyramidal cells, dopamine had a temporally biphasic effect on evoked IPSCs, producing an initial abrupt decrease in amplitude followed by a delayed increase in IPSC amplitude. Using receptor subtype- specific agonists and antagonists, we found that the initial abrupt reduction was D2 receptor- mediated, whereas the late, slower developing enhancement was D1 receptor- mediated. Linearly combining the effects of the two agonists could reproduce the biphasic dopamine effect. Because D1 agonists enhanced spontaneous (sIPSCs) but did not affect miniature (mIPSCs) IPSCs, it appears that D1 agonists caused larger evoked IPSCs by increasing the intrinsic excitability of interneurons and their axons. In contrast, D2 agonists had no effects on sIPSCs but did produce a significant reduction in mIPSCs, suggestive of a decrease in GABA release probability. In addition, D2 agonists reduced the postsynaptic response to a GABA(A) agonist. D1 and D2 receptors therefore regulated GABAergic activity in opposite manners and through different mechanisms in prefrontal cortex (PFC) pyramidal cells. This bidirectional modulation could have important implications for the computational properties of active PFC networks.