Smoothened receptor Signaling regulates the developmental shift of GABA polarity in rat somatosensory cortex

Abstract

37 Sonic Hedgehog (Shh) and its patched-smoothened receptor complex control a variety of functions in 38 the early developing central nervous system (CNS) such as neural cell proliferation and 39 differentiation. Recently, Shh signaling components have been found to be expressed at the synaptic 40 level in the postnatal and adult brain, suggesting a potential role in the regulation of synaptic 41 transmission. Here, using in utero electroporation of constitutively active and dominant-negative 42 forms of the Shh co-receptor smoothened (Smo), we studied the role of Shh signaling in the 43 development and maturation of GABAergic transmission in rat somatosensory cortex. Our results 44 show that enhancing Smo activity during development accelerates, the shift from depolarizing to 45 hyperpolarizing GABA, in a KCC2-dependent manner, rendering GABA inhibitory in immature 46 tissues. On the other hand, blocking Smo activity maintains GABA response in a depolarizing state in 47 48 Altogether, our study reveals an unexpected function of Shh signaling on the regulation of chloride 49 homeostasis through the control of KCC2 trafficking and, in particular, on the timing of the GABA 50 inhibitory/excitatory shift in brain maturation. 51 52 53