IST Austria (Institute of Science and Technology Austria), A-3400 Klosterneuburg, Austria.
J Neurosci. 2012 Oct 10;32(41):14294-304. doi: 10.1523/JNEUROSCI.6104-11.2012.
The coupling between presynaptic Ca(2+) channels and Ca(2+) sensors of exocytosis is a key determinant of synaptic transmission. Evoked release from parvalbumin (PV)-expressing interneurons is triggered by nanodomain coupling of P/Q-type Ca(2+) channels, whereas release from cholecystokinin (CCK)-containing interneurons is generated by microdomain coupling of N-type channels. Nanodomain coupling has several functional advantages, including speed and efficacy of transmission. One potential disadvantage is that stochastic opening of presynaptic Ca(2+) channels may trigger spontaneous transmitter release. We addressed this possibility in rat hippocampal granule cells, which receive converging inputs from different inhibitory sources. Both reduction of extracellular Ca(2+) concentration and the unselective Ca(2+) channel blocker Cd(2+) reduced the frequency of miniature IPSCs (mIPSCs) in granule cells by ∼50%, suggesting that the opening of presynaptic Ca(2+) channels contributes to spontaneous release. Application of the selective P/Q-type Ca(2+) channel blocker ω-agatoxin IVa had no detectable effects, whereas both the N-type blocker ω-conotoxin GVIa and the L-type blocker nimodipine reduced mIPSC frequency. Furthermore, both the fast Ca(2+) chelator BAPTA-AM and the slow chelator EGTA-AM reduced the mIPSC frequency, suggesting that Ca(2+)-dependent spontaneous release is triggered by microdomain rather than nanodomain coupling. The CB(1) receptor agonist WIN 55212-2 also decreased spontaneous release; this effect was occluded by prior application of ω-conotoxin GVIa, suggesting that a major fraction of Ca(2+)-dependent spontaneous release was generated at the terminals of CCK-expressing interneurons. Tonic inhibition generated by spontaneous opening of presynaptic N- and L-type Ca(2+) channels may be important for hippocampal information processing.
突触前 Ca(2+) 通道与胞吐 Ca(2+) 传感器的偶联是突触传递的关键决定因素。表达 parvalbumin (PV) 的中间神经元的诱发释放是由 P/Q 型 Ca(2+) 通道的纳米域偶联触发的，而含有胆囊收缩素 (CCK) 的中间神经元的释放是由 N 型通道的微域偶联产生的。纳米域偶联具有几个功能优势，包括传输的速度和效率。一个潜在的缺点是，突触前 Ca(2+) 通道的随机开放可能触发自发递质释放。我们在大鼠海马颗粒细胞中研究了这种可能性，这些细胞接收来自不同抑制性来源的会聚输入。降低细胞外 Ca(2+) 浓度和非选择性 Ca(2+) 通道阻断剂 Cd(2+) 都会使颗粒细胞中微小 IPSC (mIPSC) 的频率降低约 50%，这表明突触前 Ca(2+) 通道的开放有助于自发释放。选择性 P/Q 型 Ca(2+) 通道阻断剂 ω-agatoxin IVa 没有可检测到的作用，而 N 型阻断剂 ω-conotoxin GVIa 和 L 型阻断剂 nimodipine 都降低了 mIPSC 的频率。此外，快速 Ca(2+) 螯合剂 BAPTA-AM 和慢速螯合剂 EGTA-AM 都降低了 mIPSC 的频率，这表明 Ca(2+) 依赖性自发释放是由微域而不是纳米域偶联触发的。CB(1) 受体激动剂 WIN 55212-2 也降低了自发释放；这一作用被 ω-conotoxin GVIa 的预先应用所阻断，这表明 Ca(2+) 依赖性自发释放的主要部分是由 CCK 表达中间神经元的末端产生的。由突触前 N 型和 L 型 Ca(2+) 通道的自发开放产生的紧张性抑制可能对海马体的信息处理很重要。
