Li Yan, Chen Xin, Dzakpasu Rhonda, Conant Katherine
Department of Neuroscience, Georgetown University School of Medicine, Washington, District of Columbia, USA.
Department of Physics, Georgetown University, Washington, District of Columbia, USA.
J Neurochem. 2017 Feb;140(4):550-560. doi: 10.1111/jnc.13915. Epub 2017 Jan 12.
Oscillatory activity occurs in cortical and hippocampal networks with specific frequency ranges thought to be critical to working memory, attention, differentiation of neuronal precursors, and memory trace replay. Synchronized activity within relatively large neuronal populations is influenced by firing and bursting frequency within individual cells, and the latter is modulated by changes in intrinsic membrane excitability and synaptic transmission. Published work suggests that dopamine, a potent modulator of learning and memory, acts on dopamine receptor 1-like dopamine receptors to influence the phosphorylation and trafficking of glutamate receptor subunits, along with long-term potentiation of excitatory synaptic transmission in striatum and prefrontal cortex. Prior studies also suggest that dopamine can influence voltage gated ion channel function and membrane excitability in these regions. Fewer studies have examined dopamine's effect on related endpoints in hippocampus, or potential consequences in terms of network burst dynamics. In this study, we record action potential activity using a microelectrode array system to examine the ability of dopamine to modulate baseline and glutamate-stimulated bursting activity in an in vitro network of cultured murine hippocampal neurons. We show that dopamine stimulates a dopamine type-1 receptor-dependent increase in number of overall bursts within minutes of its application. Notably, however, at the concentration used herein, dopamine did not increase the overall synchrony of bursts between electrodes. Although the number of bursts normalizes by 40 min, bursting in response to a subsequent glutamate challenge is enhanced by dopamine pretreatment. Dopamine-dependent potentiation of glutamate-stimulated bursting was not observed when the two modulators were administered concurrently. In parallel, pretreatment of murine hippocampal cultures with dopamine stimulated lasting increases in the phosphorylation of the glutamate receptor subunit GluA1 at serine 845. This effect is consistent with the possibility that enhanced membrane insertion of GluAs may contribute to a more slowly evolving dopamine-dependent potentiation of glutamate-stimulated bursting. Together, these results are consistent with the possibility that dopamine can influence hippocampal bursting by at least two temporally distinct mechanisms, contributing to an emerging appreciation of dopamine-dependent effects on network activity in the hippocampus.
振荡活动发生在皮质和海马网络中，其特定频率范围被认为对工作记忆、注意力、神经元前体的分化以及记忆痕迹重演至关重要。相对较大的神经元群体内的同步活动受单个细胞的放电和爆发频率影响，而后者又受内在膜兴奋性和突触传递变化的调节。已发表的研究表明，多巴胺作为学习和记忆的强效调节剂，作用于多巴胺受体1样多巴胺受体，影响谷氨酸受体亚基的磷酸化和转运，以及纹状体和前额叶皮质兴奋性突触传递的长期增强。先前的研究还表明，多巴胺可影响这些区域的电压门控离子通道功能和膜兴奋性。较少有研究考察多巴胺对海马相关终点的影响，或对网络爆发动态的潜在影响。在本研究中，我们使用微电极阵列系统记录动作电位活动，以考察多巴胺在体外培养的小鼠海马神经元网络中调节基线和谷氨酸刺激的爆发活动的能力。我们发现，多巴胺在应用后数分钟内刺激多巴胺1型受体依赖性的总体爆发次数增加。然而，值得注意的是，在本文所用的浓度下，多巴胺并未增加电极间爆发的总体同步性。尽管爆发次数在40分钟时恢复正常，但多巴胺预处理可增强对随后谷氨酸刺激的爆发反应。当同时给予这两种调节剂时，未观察到多巴胺依赖性增强谷氨酸刺激的爆发。同时，用多巴胺预处理小鼠海马培养物可刺激谷氨酸受体亚基GluA1丝氨酸845位点的磷酸化持续增加。这种效应与GluA1膜插入增强可能导致谷氨酸刺激的爆发出现更缓慢演变的多巴胺依赖性增强的可能性一致。总之，这些结果与多巴胺可通过至少两种时间上不同的机制影响海马爆发的可能性一致，这有助于人们对多巴胺对海马网络活动的依赖性效应有新的认识。
