<italic>Eunice Kennedy Shriver</italic> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
Center for Genomics and Systems Biology, NYU, Abu-Dhabi, United Arab Emirates.
Elife. 2020 Feb 13;9:e51996. doi: 10.7554/eLife.51996.
In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCKVGluT3INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCKVGluT3INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCKVGluT3INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCKVGluT3INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCKVGluT3INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.
违反了戴尔原则，几种神经元亚型使用不止一种经典神经递质。囊泡谷氨酸转运体三（Vesicular Glutamate Transporter 3，VGluT3）和胆囊收缩素（Cholecystokinin，CCK）表达的皮质中间神经元（CCKVGluT3INTs）的分子鉴定促使人们猜测这些细胞可能会进行 GABA/谷氨酸共释放，尽管缺乏直接证据。我们使用配对记录和光遗传学方法，明确证明了成年小鼠中 CCKVGluT3INT 介导的 GABA/谷氨酸共传递到主细胞上。尽管在正常情况下，GABA 能抑制占主导地位，但当谷氨酸脱羧酶（Glutamate Decarboxylase，GAD）功能受损时，谷氨酸能信号变得占主导地位。CCKVGluT3INT 表现出惊人的解剖多样性，除了预期的篮状细胞外，还包括所有已知树突靶向 CCK 中间神经元的亚群，其广泛的回路支配在正常情况下极大地抑制了回路兴奋性。然而，在 CCKVGluT3INT 谷氨酸能表型被放大的情况下，它们会促进矛盾的网络过度兴奋，这可能与涉及 GAD 功能障碍的疾病有关，如精神分裂症或维生素 B6 缺乏症。
