Sonic hedgehog (Shh) and its patched–smoothened receptor complex control a variety of functions in the developing central nervous system, such as neural cell proliferation and differentiation. Recently, Shh signaling components have been found to be expressed at the synaptic level in the postnatal brain, suggesting a potential role in the regulation of synaptic transmission. Using in utero electroporation of constitutively active and negative-phenotype forms of the Shh signal transducer smoothened (Smo), we studied the role of Smo signaling in the development and maturation of GABAergic transmission in the somatosensory cortex. Our results show that enhancing Smo activity during development accelerates the shift from depolarizing to hyperpolarizing GABA in a manner dependent on functional expression of potassium–chloride cotransporter type 2 (KCC2, also known as SLC12A5). On the other hand, blocking Smo activity maintains the GABA response in a depolarizing state in mature cortical neurons, resulting in altered chloride homeostasis and increased seizure susceptibility. This study reveals unexpected functions of Smo signaling in the regulation of chloride homeostasis, through control of KCC2 cell-surface stability, and the timing of the GABA excitatory-to-inhibitory shift in brain maturation.

声波刺猬 (Shh) 及其补丁平滑受体复合物控制发育中的中枢神经系统的多种功能，例如神经细胞增殖和分化。最近，人们发现Shh信号成分在出生后大脑的突触水平上表达，表明其在调节突触传递中具有潜在作用。使用子宫内电穿孔Shh信号转导器平滑（Smo）的组成型活性和负表型形式，我们研究了Smo信号在体感皮层GABA能传递的发育和成熟中的作用。我们的结果表明，在发育过程中增强 Smo 活性会加速 GABA 从去极化向超极化的转变，其方式取决于 2 型钾氯化物协同转运蛋白（KCC2，也称为 SLC12A5）的功能表达。另一方面，阻断 Smo 活性可使成熟皮质神经元中的 GABA 反应维持在去极化状态，从而导致氯离子稳态改变并增加癫痫易感性。这项研究揭示了 Smo 信号通过控制 KCC2 细胞表面稳定性以及大脑成熟过程中 GABA 兴奋性向抑制性转变的时间，在调节氯离子稳态方面具有意想不到的功能。