Xu Fenglian, Hennessy Deirdre A, Lee Thomas K M, Syed Naweed I
Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
J Neurosci. 2009 Feb 18;29(7):2167-76. doi: 10.1523/JNEUROSCI.4682-08.2009.
Nervous system functions in all animals rely upon synaptic connectivity that is established during early development. Whereas cell-cell signaling plays a critical role in establishing synapse specificity, the involvement of extrinsic growth factors cannot, however, be undermined. We have previously demonstrated that trophic factors are required for excitatory but not inhibitory synapse formation between Lymnaea neurons. Moreover, in the absence of trophic factors, neurons from a number of species establish inappropriate inhibitory synapses, which can, however, be corrected by the addition of trophic factors. The precise site of trophic factor actions (presynaptic versus postsynaptic) and the underlying mechanisms remain, however, undefined. Here, we provide the first direct evidence that the trophic factor-mediated excitatory synapse formation involves activity-induced calcium (Ca(2+)) oscillations in the postsynaptic left pedal dorsal 1 (LPeD1) but not the presynaptic visceral dorsal 4 (VD4, cholinergic) neuron. These oscillations involved Ca(2+) influx through voltage-gated Ca(2+) channels and required receptor tyrosine kinase activity which was essential for the expression of excitatory, nicotinic acetylcholine receptors in the postsynaptic cell during synapse formation. We also demonstrate that selectively blocking the electrical activity presynaptically did not perturb trophic factor-induced synapse formation between the paired cells, whereas hyperpolarizing the postsynaptic cell prevented appropriate synaptogenesis between VD4 and LPeD1 cells. Together, our data underscore the importance of extrinsic trophic factors in regulating the electrical activity of the postsynaptic but not the presynaptic cell and that the resulting Ca(2+) oscillations are essential for the expression of postsynaptic receptors during specific synapse formation.
所有动物的神经系统功能都依赖于在早期发育过程中建立的突触连接。虽然细胞间信号传导在建立突触特异性方面起着关键作用，但外在生长因子的参与也不容小觑。我们之前已经证明，营养因子是椎实螺神经元之间兴奋性而非抑制性突触形成所必需的。此外，在缺乏营养因子的情况下，许多物种的神经元会建立不适当的抑制性突触，不过，添加营养因子可以纠正这种情况。然而，营养因子作用的确切位点（突触前还是突触后）及其潜在机制仍不明确。在这里，我们提供了首个直接证据，表明营养因子介导的兴奋性突触形成涉及突触后左足背侧1（LPeD1）神经元而非突触前内脏背侧4（VD4，胆碱能）神经元中由活动诱导的钙（Ca(2+)）振荡。这些振荡涉及通过电压门控钙通道的Ca(2+)内流，并且需要受体酪氨酸激酶活性，这对于突触形成过程中突触后细胞中兴奋性烟碱型乙酰胆碱受体的表达至关重要。我们还证明，选择性地在突触前阻断电活动不会干扰营养因子诱导的配对细胞之间的突触形成，而使突触后细胞超极化则会阻止VD4和LPeD1细胞之间的适当突触发生。总之，我们的数据强调了外在营养因子在调节突触后而非突触前细胞的电活动中的重要性，并且由此产生的Ca(2+)振荡对于特定突触形成过程中突触后受体的表达至关重要。
