Kumar S S, Faber D S
Neuroscience Graduate Group, The David Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 1999 Mar 1;19(5):1620-35. doi: 10.1523/JNEUROSCI.19-05-01620.1999.
Persistent potentiations of the chemical and electrotonic components of the eighth nerve (NVIII) EPSP recorded in vivo in the goldfish reticulospinal neuron, the Mauthner cell, can be evoked by afferent tetanization or local dendritic application of an endogenous transmitter, dopamine (3-hydroxytyramine). These modifications are attributable to the activation of distinct intracellular kinase cascades. Although dopamine-evoked potentiation (DEP) is mediated by the cAMP-dependent protein kinase (PKA), tetanization most likely activates a Ca2+-dependent protein kinase via an increased intracellular Ca2+ concentration. We present evidence that the eighth nerve tetanus that induces LTP does not act by triggering dopamine release, because it is evoked in the presence of a broad spectrum of dopamine antagonists. To test for interactions between these pathways, we applied the potentiating paradigms sequentially. When dopamine was applied first, tetanization produced additional potentiation of the mixed synaptic response, but when the sequence was reversed, DEP was occluded, indicating that the synapses potentiated by the two procedures belong to the same or overlapping populations. Experiments were conducted to determine interactions between the underlying regulatory mechanisms and the level of their convergence. Inhibiting PKA does not impede tetanus-induced LTP, and chelating postsynaptic Ca2+ with BAPTA does not block DEP, indicating that the initial steps of the induction processes are independent. Pharmacological and voltage-clamp analyses indicate that the two pathways converge on functional AMPA/kainate receptors for the chemically mediated EPSP and gap junctions for the electrotonic component or at intermediaries common to both pathways. A cellular model incorporating these interactions is proposed on the basis of differential modulation of synaptic responses via receptor-protein phosphorylation.
在金鱼的网状脊髓神经元（即莫纳细胞）中，对体内记录的第八对脑神经（NVIII）兴奋性突触后电位（EPSP）的化学和电紧张成分进行持续增强时，可通过传入纤维强直刺激或向内源性递质多巴胺（3-羟酪胺）进行局部树突应用来诱发。这些修饰归因于不同细胞内激酶级联反应的激活。虽然多巴胺诱发的增强作用（DEP）是由环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）介导的，但强直刺激很可能通过增加细胞内钙离子浓度来激活一种钙离子依赖性蛋白激酶。我们提供的证据表明，诱导长时程增强（LTP）的第八对脑神经强直刺激并非通过触发多巴胺释放起作用，因为它是在存在多种多巴胺拮抗剂的情况下诱发的。为了测试这些途径之间的相互作用，我们依次应用了增强范式。当首先应用多巴胺时，强直刺激会使混合突触反应产生额外的增强，但当顺序颠倒时，DEP会被阻断，这表明通过这两种程序增强的突触属于相同或重叠的群体。进行实验以确定潜在调节机制之间的相互作用及其汇聚水平。抑制PKA并不妨碍强直刺激诱导的LTP，用1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸（BAPTA）螯合突触后钙离子也不会阻断DEP，这表明诱导过程的初始步骤是独立的。药理学和电压钳分析表明，这两条途径在化学介导的EPSP的功能性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人藻酸（kainate）受体以及电紧张成分的缝隙连接上汇聚，或者在两条途径共有的中间环节上汇聚。基于通过受体-蛋白磷酸化对突触反应进行差异调节，提出了一个包含这些相互作用的细胞模型。
