Marron Fernandez de Velasco Ezequiel, Hearing Matthew, Xia Zhilian, Victoria Nicole C, Luján Rafael, Wickman Kevin
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Neuropharmacology. 2015 Aug;95:353-60. doi: 10.1016/j.neuropharm.2015.03.029. Epub 2015 Apr 2.
The medial prefrontal cortex (mPFC) has been implicated in multiple disorders characterized by clear sex differences, including schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, and drug addiction. These sex differences likely represent underlying differences in connectivity and/or the balance of neuronal excitability within the mPFC. Recently, we demonstrated that signaling via the metabotropic γ-aminobutyric acid receptor (GABABR) and G protein-gated inwardly-rectifying K(+) (GIRK/Kir3) channels modulates the excitability of the key output neurons of the mPFC, the layer 5/6 pyramidal neurons. Here, we report a sex difference in the GABABR-GIRK signaling pathway in these neurons. Specifically, GABABR-dependent GIRK currents recorded in the prelimbic region of the mPFC were larger in adolescent male mice than in female counterparts. Interestingly, this sex difference was not observed in layer 5/6 pyramidal neurons of the adjacent infralimbic cortex, nor was it seen in young adult mice. The sex difference in GABABR-GIRK signaling is not attributable to different expression levels of signaling pathway components, but rather to a phosphorylation-dependent trafficking mechanism. Thus, sex differences related to some diseases associated with altered mPFC function may be explained in part by sex differences in GIRK-dependent signaling in mPFC pyramidal neurons.
内侧前额叶皮质（mPFC）与多种具有明显性别差异的疾病有关，包括精神分裂症、注意力缺陷多动障碍、创伤后应激障碍、抑郁症和药物成瘾。这些性别差异可能代表了mPFC内连接性和/或神经元兴奋性平衡的潜在差异。最近，我们证明通过代谢型γ-氨基丁酸受体（GABABR）和G蛋白门控内向整流钾（GIRK/Kir3）通道进行的信号传导可调节mPFC关键输出神经元（5/6层锥体神经元）的兴奋性。在此，我们报告了这些神经元中GABABR-GIRK信号通路的性别差异。具体而言，在mPFC前边缘区记录到的GABABR依赖性GIRK电流在青春期雄性小鼠中比雌性小鼠更大。有趣的是，在相邻的边缘下皮质的5/6层锥体神经元中未观察到这种性别差异，在成年小鼠中也未观察到。GABABR-GIRK信号传导中的性别差异并非归因于信号通路成分的不同表达水平，而是归因于一种磷酸化依赖性转运机制。因此，与mPFC功能改变相关的某些疾病的性别差异可能部分由mPFC锥体神经元中GIRK依赖性信号传导的性别差异来解释。
