Rombo Diogo M, Newton Kathryn, Nissen Wiebke, Badurek Sylvia, Horn Jacqueline M, Minichiello Liliana, Jefferys John G R, Sebastiao Ana M, Lamsa Karri P
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Portugal; Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Portugal; Department of Pharmacology, Oxford University, Oxford, United Kingdom.
Hippocampus. 2015 May;25(5):566-80. doi: 10.1002/hipo.22392. Epub 2014 Nov 29.
Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2A R activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2A R's facilitatory effect on cortical network activity.
腺苷通过腺苷A1受体广泛抑制大脑中的兴奋性神经元，但腺苷A2A受体（A2A R）的激活具有相反的作用，可促进神经网络中的放电。在海马体中，A2A R的表达水平较低，且该受体对已确定的神经元回路的影响尚不清楚。利用光遗传学传入刺激和对已确定的突触后神经元进行全细胞记录，我们发现A2A R促进了从兴奋性谷氨酸能的谢弗侧支到CA1锥体细胞的突触传递，但对γ-氨基丁酸（GABA）能抑制性中间神经元则无此作用。此外，A2A R增强了CA1区中间神经元之间的GABA能抑制性传递，导致锥体细胞去抑制。腺苷A2A R对到锥体细胞的GABA能突触没有直接调节作用。因此，腺苷A2A R的激活改变了CA1区的突触兴奋 - 抑制平衡，导致锥体细胞对谷氨酸能谢弗侧支刺激的放电增加。与此一致的是，我们发现A2A R在细胞外钾升高的过度兴奋条件下或高频电刺激后促进锥体细胞同步放电。我们的结果揭示了海马体CA1区中腺苷A2A R在突触和细胞类型上的选择性作用。所揭示的机制有助于我们理解A2A R对皮质网络活动的促进作用。
