Glutamate released during normal synaptic transmission is sufficient to induce astrocytic Ca 2+ oscillations ( Dani et al., 1992 Wang et al., 2006), which trigger Ca 2+ elevation in co-cultured neurons ( Nedergaard, 1994 Parpura et al., 1994) that can elicit action potentials ( Angulo et al., 2004 Fellin et al., 2006 Fellin et al., 2004 Pirttimaki et al., 2011). Cultured astrocytes oscillate intracellular Ca 2+ spontaneously ( Takata and Hirase, 2008) and in response to neurotransmitters ( Agulhon et al., 2008 Lee et al., 2010), including glutamate ( Cornell-Bell et al., 1990). A single astrocytic glia contacts multiple neuronal cell bodies, hundreds of neuronal processes, and tens of thousands of synapses ( Halassa et al., 2007 Ventura and Harris, 1999). In the cortex, glia and neurons exist in equal abundance ( Azevedo et al., 2009) and are intimately associated.
However, growing evidence indicates glial Ca 2+ signaling influences neuronal physiology on a rapid time scale. Glial cells are well known to play structural and supportive roles for their more electrically excitable neuronal counterparts. These findings indicate cortex glial Ca 2+ couples to K + buffering through calcineurin regulated endo-exocytotic balance and K 2P channel expression to modulate neuronal excitability. Restoring glial K + buffering by overexpressing a leak K + channel rescues zydeco seizures. Knockdown of sandman, a K2P channel, recapitulates NCKX zydeco seizures. Our results indicate elevation of glial Ca 2+ causes hyperactivation of calcineurin-dependent endocytosis and accumulation of early endosomes.
To determine how cortex glial Ca 2+ signaling controls neuronal excitability, an in vivo modifier screen for the NCKX zydeco seizure phenotype was performed. Mutations in the cortex glial NCKX exchanger zydeco abolish microdomain Ca 2+ oscillatory activity and elevate glial Ca 2+, predisposing animals to seizures. Drosophila cortex glia are restricted to brain regions devoid of synapses, providing an opportunity to characterize interactions between glia and neuronal somas. Glial-neuronal signaling at synapses is widely appreciated, but how glia interact with neuronal cell bodies is less clear.
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