A rare mutation affecting the Forkhead-box protein P2 (FOXP2) transcription factor causes a severe monogenic speech and language disorder. Mice carrying an identical point mutation to that observed in affected patients (Foxp2^+/R552H mice) display motor deficits and impaired synaptic plasticity in the striatum. However, the consequences of the mutation on neuronal function, in particular in the cerebral cortex, remain little studied. Foxp2 is expressed in a subset of Layer VI cortical neurons. Here, we used Ntsr1-EGFP mice to identify Foxp2+ neurons in the mouse auditory cortex ex vivo. We studied the functional impact of the R552H mutation on the morphologic and functional properties of Layer VI cortical neurons from Ntsr1-EGFP; Foxp2^+/R552H male and female mice. The complexity of apical, but not basal dendrites was significantly lower in Foxp2^+/R552H cortico-thalamic neurons than in control Foxp2^+/+ neurons. Excitatory synaptic inputs, but not inhibitory synaptic inputs, were decreased in Foxp2^+/R552H mice. In response, homeostatic mechanisms would be expected to increase neuronal gain, i.e., the conversion of a synaptic input into a firing output. However, the intrinsic excitability of Foxp2+ cortical neurons was lower in Foxp2^+/R552H neurons. A-type and delayed-rectifier (DR) potassium currents, two putative transcriptional targets of Foxp2, were not affected by the mutation. In contrast, GABA_B/GIRK signaling, another presumed target of Foxp2, was increased in mutant neurons. Blocking GIRK channels strongly attenuated the difference in intrinsic excitability between wild-type (WT) and Foxp2^+/R552H neurons. Our results reveal a novel role for Foxp2 in the control of neuronal input/output homeostasis.

SIGNIFICANCE STATEMENT Mutations of the Forkhead-box protein 2 (FOXP2) gene in humans are the first known monogenic cause of a speech and language disorder. The Foxp2 mutation may directly affect neuronal development and function in neocortex, where Foxp2 is expressed. Brain imaging studies in patients with a heterozygous mutation in FOXP2 showed abnormalities in cortical language-related regions relative to the unaffected members of the same family. However, the role of Foxp2 in neocortical neurons is poorly understood. Using mice with a Foxp2 mutation equivalent to that found in patients, we studied functional modifications in auditory cortex neurons ex vivo. We found that mutant neurons exhibit alterations of synaptic input and GABAB/GIRK signaling, reflecting a loss of neuronal homeostasis.

影响Forkhead-box蛋白P2（FOXP2）转录因子的罕见突变会导致严重的单基因语音和语言障碍。携带与受影响患者（Foxp2 ^{+ / R552H}小鼠）中观察到的点突变相同的小鼠表现出运动缺陷和纹状体中突触可塑性受损。然而，该突变对神经元功能，特别是在大脑皮层中的功能的影响，仍然很少研究。Foxp2在第六层皮质神经元的子集中表达。在这里，我们使用Ntsr1-EGFP小鼠在离体小鼠听觉皮层中识别Foxp2 +神经元。我们研究了R552H突变对Ntsr1-EGFP的第VI层皮质神经元的形态和功能特性的功能影响；Foxp2 ^{+ / R552H}雄性和雌性小鼠。Foxp2 ^{+ / R552H}皮质-丘脑神经元的顶端而不是基底树突的复杂性明显低于对照Foxp2 ^{+ / +}神经元。Foxp2 ^{+ / R552H}小鼠减少了兴奋性突触输入，但没有抑制性突触输入。作为响应，体内平衡机制有望增加神经元增益，即突触输入到放电输出的转换。但是，Foxp2 ^{+ / R552H}神经元的Foxp2 +皮质神经元的固有兴奋性较低。A型和延迟整流器（DR）钾电流，Foxp2的两个假定的转录目标，不受突变的影响。相反，GABA _B/ GIRK信号，Foxp2的另一个假定目标，突变神经元中增加。阻止GIRK通道大大减弱了野生型（WT）和Foxp2 ^{+ / R552H}神经元之间内在兴奋性的差异。我们的结果揭示了Foxp2在控制神经元输入/输出稳态中的新作用。

重要声明人类中的Forkhead-box蛋白2（FOXP2）基因突变是语音和语言障碍的第一个已知的单基因病因。Foxp2突变可能直接影响表达Foxp2的新皮层的神经元发育和功能。对FOXP2杂合突变患者的脑成像研究显示，与同一个家族的未受影响成员相比，皮质语言相关区域异常。但是，Foxp2在新皮层神经元中的作用了解甚少。我们使用具有与患者相同的Foxp2突变的小鼠，研究了离体听觉皮层神经元的功能修饰。我们发现突变神经元展示突触输入和GABAB / GIRK信号的变化，反映了神经元稳态的损失。