Dysfunction of the infralimbic cortical (ILC) region of the medial prefrontal cortex (mPFC) is thought to be an underlying factor in both affect- and cognition-related behavioral deficits that co-occur across neuropsychiatric disorders. Increasing evidence highlights pathological imbalances in prefrontal pyramidal neuron excitability and associated aberrant firing as an underlying factor in this dysfunction. G protein-gated inwardly rectifying K⁺ (GIRK/Kir3) channels mediate excitability of mPFC pyramidal neurons, however the functional role of these channels in ILC-dependent regulation of behavior and pyramidal neuron excitation is unknown. The present study used a viral-cre approach in male mice harboring a ‘floxed’ version of the kcnj3 (Girk1) gene, to disrupt GIRK1-containing channel expression in pyramidal neurons within the ILC. Loss of GIRK1-dependent signaling increased excitability and spike firing of pyramidal neurons but did not alter affective behavior measured in an elevated plus maze, forced swim test, or progressive ratio test of motivation. Alternatively, ablation of GIRK1 impaired performance in an operant-based attentional set-shifting task designed to assess cognitive flexibility. These data highlight a unique role for GIRK1 signaling in ILC pyramidal neurons in the regulation of strategy shifting but not affect and suggest that these channels may represent a therapeutic target for treatment of cognitive deficits in neuropsychiatric disease.

内侧前额叶皮层 (mPFC) 的下边缘皮质 (ILC) 区域的功能障碍被认为是在神经精神疾病中同时发生的情感和认知相关行为缺陷的潜在因素。越来越多的证据强调前额锥体神经元兴奋性的病理失衡和相关的异常放电是这种功能障碍的潜在因素。G 蛋白门控内向整流K ⁺(GIRK/Kir3) 通道介导 mPFC 锥体神经元的兴奋性，但这些通道在 ILC 依赖性行为调节和锥体神经元兴奋中的功能作用尚不清楚。本研究在含有“floxed”版本的 kcnj3 (Girk1) 基因的雄性小鼠中使用了一种病毒 cre 方法，以破坏 ILC 内锥体神经元中含有 GIRK1 的通道表达。GIRK1 依赖信号的丢失增加了锥体神经元的兴奋性和尖峰放电，但没有改变在高架十字迷宫、强迫游泳测试或动机的渐进比率测试中测量的情感行为。或者，在旨在评估认知灵活性的基于操作的注意力转移任务中，消融 GIRK1 会损害性能。