Li Min-Xu, Jia Min, Yang Li-Xia, Jiang Hao, Lanuza Maria A, Gonzalez Carmen M, Nelson Phillip G
Section on Neurobiology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutesof Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2004 Apr 14;24(15):3762-9. doi: 10.1523/JNEUROSCI.3930-03.2004.
PKC plays a critical role in competitive activity-dependent synapse modification at the neuromuscular synapse in vitro and in vivo. This action involves a reduction of the strength of inactive inputs to muscle cells that are activated by other inputs. A decrease of postsynaptic responsiveness and a loss of postsynaptic acetyl choline receptors account for the heterosynaptic loss in vitro. The loss is not seen in preparations in which PKC has been blocked pharmacologically. Here, we show that the loss does not occur in in vitro preparations made from animals genetically modified to lack the theta isoform of PKC. Synapse elimination in the newborn period in vivo is delayed but is eventually expressed in knock-out animals. PKC-dependent synapse reduction is suppressed in heterologous cultures combining normal nerve and PKC theta-deficient muscle, as might be expected from the postsynaptic locus of the changes that underlie the activity-dependent plasticity. Preparations in which PKC theta-deficient neurons innervated normal muscle also exhibited a marked deficit in PKC-deficient synapse reduction. The presynaptic action of PKC theta implied by this observation is blocked by TTX, and we propose that activity-related synapse strengthening is decreased by presynaptic PKC theta. Thus, PKC theta in both presynaptic and postsynaptic elements plays a critical role in activity-dependent synapse modulation and loss. We provide a model for activity-dependent synapse loss incorporating these findings.
蛋白激酶C（PKC）在体外和体内的神经肌肉突触处，对依赖于竞争性活动的突触修饰起着关键作用。这一作用涉及降低被其他输入激活的肌肉细胞中无活性输入的强度。突触后反应性的降低和突触后乙酰胆碱受体的丧失导致了体外异突触丧失。在药理学上阻断PKC的制剂中未观察到这种丧失。在此，我们表明，在由基因改造后缺乏PKCθ亚型的动物制成的体外制剂中不会发生这种丧失。体内新生期的突触消除被延迟，但最终在基因敲除动物中表现出来。正如从依赖活动的可塑性所基于的变化的突触后位点所预期的那样，在正常神经和PKCθ缺陷型肌肉相结合的异源培养物中，PKC依赖性突触减少受到抑制。PKCθ缺陷型神经元支配正常肌肉的制剂在PKC缺陷型突触减少方面也表现出明显的缺陷。这一观察结果所暗示的PKCθ的突触前作用被河豚毒素阻断，我们提出突触前PKCθ会降低与活动相关的突触增强。因此，突触前和突触后元件中的PKCθ在依赖活动的突触调节和丧失中都起着关键作用。我们提供了一个纳入这些发现的依赖活动的突触丧失模型。
