Abstract
ABSTRACTSonic 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.
Highlights
Sonic hedgehog (Shh) is an activity-dependent secreted synaptic molecule (Beug et al, 2011)
Using in utero electroporation of constitutively active and dominant-negative forms of the Shh co-receptor 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 dependence on functional expression of potassium-chloride cotransporter type 2 (KCC2)
Summary
Sonic hedgehog (Shh) is an activity-dependent secreted synaptic molecule (Beug et al, 2011). Shh was reported to exert a modulatory action on neuronal electrical activity in the adult brain (Bezard et al, 2003; Pascual et al, 2005) and more recently Shh signaling has been shown to regulates the formation of glutamatergic and GABAergic terminals in hippocampal neurons (Mitchell et al, 2012) These morphological changes were accompanied by an increase in the frequency of excitatory postsynaptic currents (Feng et al, 2016; Mitchell et al, 2012). Both in human and animal models accumulating evidences indicate that impairment of Shh pathway at postnatal stages may contribute for the emergence of neurodevelopmental disorders, including autism spectrum disorders (ASD) (Al-Ayadhi, 2012; Halepoto et al, 2015) and seizures (Feng et al, 2016; Su et al, 2017)
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