Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits

CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. The general excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor event in the cells’ whole transcriptome, can underlie distinct cell-type identity.胆囊收缩素表达型中间神经元（CCK-expressing interneurons，CCK+INs）在调控海马活动中发挥关键作用。本研究在大鼠CA3区中发现两类CCK+INs的放电表型：一类具有此前未被报道的膜电位依赖性放电模式，另一类为常规放电模式，二者的差异源于不同的低电压激活钾电流（low-voltage-activated potassium currents）。由于前者在模拟生理状态下的8-15Hz振荡活动中基本处于沉默状态，因此这两种不同的兴奋性特性决定了两类细胞具有截然不同的功能。 令人意外的是，两类细胞的整体兴奋性、形态学特征以及基因表达谱均极为相似，即便Kv4.3通道（Kv4.3 channels）的表达水平也无显著差异——尽管已有研究表明，Kv4.3介导的电流是造成其放电特性差异的基础。 与之相反，两类细胞的放电表型与Kv4辅助亚基的不同亚型表达密切相关，具体为KChIP1与KChIP4e、DPP6S的差异表达。 本研究揭示了此前尚未被认知的两类CCK+INs的潜在作用机制，并证实，少数基因的可变剪接——尽管这在细胞整体转录组中仅属于微小事件——即可作为独特细胞类型身份的核心调控基础。