Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
J Neurosci. 2011 Sep 21;31(38):13546-61. doi: 10.1523/JNEUROSCI.2781-11.2011.
Release of conventional neurotransmitters is mainly controlled by calcium (Ca²⁺) influx via high-voltage-activated (HVA), Ca(v)2, channels ("N-, P/Q-, or R-types") that are opened by action potentials. Regulation of transmission by subthreshold depolarizations does occur, but there is little evidence that low-voltage-activated, Ca(v)3 ("T-type"), channels take part. GABA release from cortical perisomatic-targeting interneurons affects numerous physiological processes, and yet its underlying control mechanisms are not fully understood. We investigated whether T-type Ca²⁺ channels are involved in regulating GABA transmission from these cells in rat hippocampal CA1 using a combination of whole-cell voltage-clamp, multiple-fluorescence confocal microscopy, dual-immunolabeling electron-microscopy, and optogenetic methods. We show that Ca(v)3.1, T-type Ca²⁺ channels can be activated by α3β4 nicotinic acetylcholine receptors (nAChRs) that are located on the synaptic regions of the GABAergic perisomatic-targeting interneuronal axons, including the parvalbumin-expressing cells. Asynchronous, quantal GABA release can be triggered by Ca²⁺ influx through presynaptic T-type Ca²⁺ channels, augmented by Ca²⁺ from internal stores, following focal microiontophoretic activation of the α3β4 nAChRs. The resulting GABA release can inhibit pyramidal cells. The T-type Ca²⁺ channel-dependent mechanism is not dependent on, or accompanied by, HVA channel Ca²⁺ influx, and is insensitive to agonists of cannabinoid, μ-opioid, or GABA(B) receptors. It may therefore operate in parallel with the normal HVA-dependent processes. The results reveal new aspects of the regulation of GABA transmission and contribute to a deeper understanding of ACh and nicotine actions in CNS.
传统神经递质的释放主要受钙（Ca²⁺）内流的控制，钙内流通过高电压激活（HVA）、Ca(v)2 通道（“N-、P/Q-或 R-型”），这些通道由动作电位打开。亚阈去极化对传递的调节确实会发生，但几乎没有证据表明低电压激活的 Ca(v)3（“T-型”）通道参与其中。皮质体靶向中间神经元的 GABA 释放会影响许多生理过程，但它的潜在控制机制尚未完全理解。我们使用全细胞膜片钳、多荧光共聚焦显微镜、双免疫标记电子显微镜和光遗传学方法，研究了 T 型 Ca²⁺通道是否参与调节大鼠海马 CA1 中这些细胞的 GABA 传递。我们表明，位于 GABA 能体靶向中间神经元轴突突触区域的 α3β4 烟碱型乙酰胆碱受体（nAChRs）可以激活 Ca(v)3.1、T 型 Ca²⁺通道。包括表达 parvalbumin 的细胞在内的突触后 T 型 Ca²⁺通道的 Ca²⁺内流可以触发异步、量子 GABA 释放，这种释放可通过轴突上的α3β4 nAChRs 的局部微电泳刺激来增强 Ca²⁺内流。随后的 GABA 释放可以抑制锥体细胞。这种 T 型 Ca²⁺通道依赖性机制不依赖于或伴随着 HVA 通道 Ca²⁺内流，并且对大麻素、μ-阿片和 GABA(B)受体激动剂不敏感。因此，它可能与正常的 HVA 依赖性过程并行运作。研究结果揭示了 GABA 传递调节的新方面，并有助于深入了解中枢神经系统中 ACh 和尼古丁的作用。
