Department of Neurobiology, CHS 73-235, David Geffen School of Medicine at the University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA.
Neuroscience. 2012 Jan 27;202:371-83. doi: 10.1016/j.neuroscience.2011.11.056. Epub 2011 Dec 3.
The neuropeptide cholecystokinin (CCK) is abundant in the CNS and is expressed in a subset of inhibitory interneurons, particularly in their axon terminals. The expression profile of CCK undergoes numerous changes in several models of temporal lobe epilepsy. Previous studies in the pilocarpine model of epilepsy have shown that CCK immunohistochemical labeling is substantially reduced in several regions of the hippocampal formation, consistent with decreased CCK expression as well as selective neuronal degeneration. However, in a mouse pilocarpine model of recurrent seizures, increases in CCK-labeling also occur and are especially striking in the hippocampal dendritic layers of strata oriens and radiatum. Characterizing these changes and determining the cellular basis of the increased labeling were the major goals of the current study. One possibility was that the enhanced CCK labeling could be associated with an increase in GABAergic terminals within these regions. However, in contrast to the marked increase in CCK-labeled structures, labeling of GABAergic axon terminals was decreased in the dendritic layers. Likewise, cannabinoid receptor 1-labeled axon terminals, many of which are CCK-containing GABAergic terminals, were also decreased. These findings suggested that the enhanced CCK labeling was not due to an increase in GABAergic axon terminals. The subcellular localization of CCK immunoreactivity was then examined using electron microscopy, and the identities of the structures that formed synaptic contacts were determined. In pilocarpine-treated mice, CCK was observed in dendritic spines and these were proportionally increased relative to controls, whereas the proportion of CCK-labeled terminals forming symmetric synapses was decreased. In addition, CCK-positive axon terminals forming asymmetric synapses were readily observed in these mice. Double labeling with vesicular glutamate transporter 1 and CCK revealed colocalization in numerous terminals forming asymmetric synapses, confirming the glutamatergic identity of these terminals. These data raise the possibility that expression of CCK is increased in hippocampal pyramidal cells in mice with recurrent, spontaneous seizures.
胆囊收缩素（CCK）是一种丰富的神经肽，在中枢神经系统中表达，并存在于抑制性中间神经元亚群中，尤其是其轴突末梢。在几种颞叶癫痫模型中，CCK 的表达谱发生了许多变化。在匹罗卡品癫痫模型的先前研究中，已经表明在海马结构的几个区域中，CCK 免疫组织化学标记显著减少，这与 CCK 表达减少以及选择性神经元变性一致。然而，在反复癫痫发作的小鼠匹罗卡品模型中，CCK 标记也会增加，并且在海马的锥体细胞层和辐射层的树突层中尤为明显。描述这些变化并确定增加标记的细胞基础是当前研究的主要目标。一种可能性是，增强的 CCK 标记可能与这些区域内 GABA 能末梢的增加有关。然而，与标记结构的显著增加相反，树突层中的 GABA 能轴突末梢的标记减少了。同样，大麻素受体 1 标记的轴突末梢（其中许多是包含 CCK 的 GABA 能末梢）也减少了。这些发现表明，增强的 CCK 标记不是由于 GABA 能轴突末梢的增加所致。然后使用电子显微镜检查 CCK 免疫反应性的亚细胞定位，并确定形成突触接触的结构的身份。在匹罗卡品处理的小鼠中，在树突棘中观察到 CCK，与对照组相比，其比例相对增加，而形成对称突触的 CCK 标记末梢的比例减少。此外，在这些小鼠中容易观察到形成不对称突触的 CCK 阳性轴突末梢。与囊泡谷氨酸转运体 1 和 CCK 的双重标记显示，在形成不对称突触的许多末梢中存在共定位，证实了这些末梢的谷氨酸能特性。这些数据表明，在具有反复性、自发性癫痫发作的小鼠中，CCK 在海马锥体神经元中的表达增加。
