Sonic Hedgehog Signaling (Shh) regulates the developmental shift of GABA polarity in rat somatosensory cortex

Sonic Hedgehog (Shh) and its patched-smoothened receptor complex control a variety of functions in the early developing central nervous system (CNS) such as neural cell proliferation and differentiation. Recently, Shh signaling components have been found to be expressed at the synaptic level in the postnatal and adult brain, suggesting a potential role in the regulation of synaptic transmission. Here, using electroporation of constitutively active and dominant-negative forms of the Shh co-receptor smoothened (Smo), we studied the role of Shh signaling in the development and maturation of GABAergic transmission in rat somatosensory cortex. Our results show that enhancing Smo activity during development accelerates, the shift from depolarizing to hyperpolarizing GABA, in a KCC2-dependent manner, rendering GABA inhibitory in immature tissues. On the other hand, blocking Smo activity maintains GABA response in a depolarizing state in mature cortical neurons resulting in altered chloride homeostasis and increased seizure susceptibility. Altogether, our study reveals an unexpected function of Shh signaling on the regulation of chloride homeostasis through the control of KCC2 trafficking and, in particular, on the timing of the GABA inhibitory/excitatory shift in brain maturation.