Axo-somatic K⁺ channels control action potential output in part by acting in concert with voltage-gated Na⁺channels to set action potential threshold. Slowly inactivating, D-type K⁺ channels are enriched at the axo-somatic region of cortical pyramidal neurons of the prefrontal cortex where they regulate action potential firing. We previously demonstrated that D-type K⁺ channels are down regulated in extratelencephalic-projecting (ET) L5 neurons in the medial prefrontal cortex of the fmr1 knockout mouse model of Fragile X syndrome (FX mice), resulting in a hyperpolarized action potential threshold. To test whether K⁺ channel alterations are regulated in a cell autonomous manner in FXS, we used a viral-mediated approach to restore expression of Fragile X Mental Retardation Protein (FMRP) in a small population of prefrontal neurons in male FX mice. Outside-out voltage clamp recordings revealed a higher D-type K⁺ conductance in FMRP-positive ET neurons compared to nearby FMRP-negative ET neurons. FMRP did not affect either rapidly inactivating A-type or non-inactivating K⁺ conductance. ET neuron patches recorded with FMRP_1-298, a truncated form of FMRP which lacks mRNA binding domains, included in the pipette solution had larger D-type K⁺ conductance compared to heat-inactivated controls. Viral expression of FMRP in FX mice depolarized action potential threshold to near wild type levels in ET neurons. These results suggest that FMRP influences the excitability of ET neurons in the mPFC by regulating somatic D-type K⁺ channels in a cell autonomous, protein-protein dependent manner.

中文翻译：

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Fragile X Mental Retardation Protein 调节小鼠前额叶皮层的体细胞 D 型 K+ 通道和动作电位阈值

轴突 K ⁺通道部分地通过与电压门控 Na ⁺通道协同作用来设置动作电位阈值来控制动作电位输出。缓慢失活的 D 型 K ⁺通道在前额叶皮层皮质锥体神经元的轴突区域富集，在那里它们调节动作电位放电。我们之前已经证明，在脆性 X 综合征（FX 小鼠）的 fmr1 敲除小鼠模型的内侧前额叶皮层中，D 型 K ⁺通道在脑外投射 (ET) L5 神经元中下调，导致超极化动作电位阈值。测试是否 K ⁺通道改变在 FXS 中以细胞自主方式受到调节，我们使用病毒介导的方法来恢复雄性 FX 小鼠前额叶神经元小群中脆性 X 精神发育迟缓蛋白 (FMRP) 的表达。外部电压钳记录显示，与附近的 FMRP 阴性 ET 神经元相比，FMRP 阳性 ET 神经元中的D 型 K ⁺电导更高。FMRP 不影响快速灭活 A 型或非灭活 K ⁺电导。用 FMRP _1-298记录的 ET 神经元贴片，FMRP的截短形式，缺少 mRNA 结合域，包含在移液管溶液中具有较大的 D 型 K ⁺与热灭活对照相比的电导。FX 小鼠中 FMRP 的病毒表达使 ET 神经元中的动作电位阈值去极化至接近野生型水平。这些结果表明，FMRP 通过以细胞自主、蛋白质-蛋白质依赖性方式调节体细胞 D 型 K ⁺通道来影响 mPFC 中 ET 神经元的兴奋性。