Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling in mature astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.
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...
Cortical systems maintain and process information through the sustained activation of recurrent local networks of neurons. Layer 5 is known to have a major role in generating the recurrent activation associated with these functions, but relatively little is known about its intrinsic dynamics at the mesoscopic level of large numbers of neighboring neurons. Using calcium imaging, we measured the spontaneous activity of networks of deep-layer medial prefrontal cortical neurons in an acute slice model. Inferring the simultaneous activity of tens of neighboring neurons, we found that while the majority showed only sporadic activity, a subset of neurons engaged in sustained delta frequency rhythmic activity. Spontaneous activity under baseline conditions was weakly correlated between pairs of neurons, and rhythmic neurons showed little coherence in their oscillations. However, we consistently observed brief bouts of highly synchronous activity that must be attributed to network activity. NMDA-mediated stimulation enhanced rhythmicity, synchrony, and correlation within these local networks. These results characterize spontaneous prefrontal activity at a previously unexplored spatiotemporal scale and suggest that medial prefrontal cortex can act as an intrinsic generator of delta oscillations. Using calcium imaging and a novel analytic framework, we characterized the spontaneous and NMDA-evoked activity of layer 5 prefrontal cortex at a largely unexplored spatiotemporal scale. Our results suggest that the mPFC microcircuitry is capable of intrinsically generating delta oscillations and sustaining synchronized network activity that is potentially relevant for understanding its contribution to cognitive processes.
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