Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization

Abstract

20Astrocytes have emerged as integral partners with neurons in regulating synapse formation and 21 function, but the mechanisms that mediate these interactions are not well understood. Here, we 22 show that Sonic hedgehog (Shh) signaling in mature astrocytes is required for establishing 23 structural organization and remodeling of cortical synapses in a cell type-specific manner. In 24 the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized 25 primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a 26 dramatic increase in synapse number specifically on layer V apical dendrites that emerges 27 during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is 28 impaired in mutant mice and is accompanied by an increase in neuronal excitability and a 29 reduction of the glial-specific, inward-rectifying K + channel Kir4.1. These data identify a critical 30 role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for 31 sculpting synapses. 32 33 34 35 36 42Astrocytes interact intimately with synapses to regulate their formation, maturation, and function, 43 and a growing number of astrocyte-secreted proteins that directly mediate synapse formation 44 and elimination have been identified 5-9 . In addition, astrocytes regulate concentrations of K + 45 and glutamate in the extracellular space, thereby modulating neuronal activity 10 . Nevertheless, 46 despite the remarkable progress in our understanding of the essential role for astrocytes in 47 regulating synaptic formation and function, the underlying signaling programs mediating 48 astrocyte-dependent regulation of synapse organization remain poorly understood. 49The molecular signaling pathway Sonic hedgehog (Shh) governs a broad array of 50 neurodevelopmental processes in the vertebrate embryo, including morphogenesis, cell 51 proliferation and specification, and axon pathfinding 11,12 . However, Shh activity persists in 52 multiple cell populations in the postnatal and adult CNS, including progenitor cells, as well as in 53 differentiated neurons and astrocytes [13][14][15][16][17] , where novel and unexpected roles for Shh activity 54 are emerging 18 . Following injury, Shh has been shown to mitigate inflammation 19,20 , and in the 55 cerebellum, Shh derived from Purkinje neurons instructs phenotypic properties of mature 56 Bergmann glia 21 . In the postnatal cortex, Shh is required for establishing local circuits between 57 two distinct projection neuron populations 16 . Shh produced by layer V neurons guides the 58 formation of synaptic connections to its layer II/III presynaptic partners, which transduce the Shh 59 signal through non-canonical, Gli-independent mechanisms. We have previously shown that 60 Shh signaling is also active in a discrete subpopulation of cortical astrocytes 17 , suggesting that 61 Shh signaling mediates both homotypic and heterotypic cellular interactions. Astrocytes 62 engaging in Shh activity are iden...

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

“…Sonic hedgehog (Shh) and its receptor Boc are both known to be expressed exclusively by specific subpopulations of subcortical and intracortical projection neurons, respectively (Harwell et al 2012). Astrocytes in a number of CNS regions are known to be responsive to Shh signaling (Farmer et al 2016, Garcia et al 2010, Hill et al 2019).…”

“…Shh is expressed by subcortical projection neurons in cortical layer V, where it has been shown to regulate the specific patterns of intracortical circuitry (Harwell et al 2012). Shh signaling is active in a subpopulation of mature astrocytes that are localized primarily to the deep layers of the cortex (Garcia et al 2010, Hill et al 2019). In the cerebellum and cortex, Shh signaling in astrocytes promotes the expression of the inward rectifying potassium channel Kir4.1, which is critical for regulating potassium buffering and neuronal excitability (Farmer et al 2016, Hill et al 2019.…”

“…Shh signaling is active in a subpopulation of mature astrocytes that are localized primarily to the deep layers of the cortex (Garcia et al 2010, Hill et al 2019). In the cerebellum and cortex, Shh signaling in astrocytes promotes the expression of the inward rectifying potassium channel Kir4.1, which is critical for regulating potassium buffering and neuronal excitability (Farmer et al 2016, Hill et al 2019. In this study we identify the complement of molecular programs driven by Shh signaling in cortical astrocytes and show that neuron-derived Shh is both necessary and sufficient to promote astrocyte morphogenesis and the layer-specific enrichment of genes in astrocytes involved in regulating synapse formation and function.…”

Effect of TO901317 on promoting the differentiation of human bone marrow mesenchymal stem cells into dopamine neurons on Parkinson's disease

“…SHH participates in a broad array of neurodevelopmental processes in the vertebrate embryo, including morphogenesis, cell proliferation and speci cation, and axon path nding 55,56 . SHH exists in the postnatal and adult CNS, such as modulation of neuronal activity, progenitor cells and astrocytes as well as in differentiated neurons [57][58][59] .…”

Therapeutic effect of TO901317 on 6-OHDA-induced Parkinson rats in vitro and in vivo

“…SHH participates in a broad array of neurodevelopmental processes in the vertebrate embryo, including morphogenesis, cell proliferation and specification, and axon pathfinding 51,52 . SHH exists in the postnatal and adult CNS, such as modulation of neuronal activity, progenitor cells and astrocytes as well as in differentiated neurons [53][54][55] . FGF8 is essential for the development of multiple brain regions, such as suprachiasmatic nuclei (SCN) and hypothalamo-pituitary 56,57 .…”