Glial Ca2+ signaling links endocytosis to K+ buffering around neuronal somas to regulate excitability

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Abstract

Glial-neuronal signaling at synapses is widely studied, but how glia interact with neuronal somas to regulate neuronal function is unclear. Drosophila cortex glia are restricted to brain regions devoid of synapses, providing an opportunity to characterize interactions with neuronal somas. Mutations in the cortex glial NCKX^zydeco elevate basal Ca²⁺, predisposing animals to seizure-like behavior. To determine how cortex glial Ca²⁺ signaling controls neuronal excitability, we performed an in-vivo modifier screen of the NCKX^zydecoseizure phenotype. We show that elevation of glial Ca²⁺ causes hyperactivation of calcineurin-dependent endocytosis and accumulation of early endosomes. Knockdown of sandman, a K_2P channel, recapitulates NCKX^zydeco seizures. Indeed, sandman expression on cortex glial membranes is substantially reduced in NCKX^zydeco mutants, indicating enhanced internalization of sandman predisposes animals to seizures. These data provide an unexpected link between glial Ca²⁺ signaling and the well-known role of glia in K⁺ buffering as a key mechanism for regulating neuronal excitability.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Shirley Weiss

The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States

For correspondence
s_weiss@MIT.EDU

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1006-349X
Jan E Melom

The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Kiel G Ormerod

The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Yao V Zhang

The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
J Troy Littleton

The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5576-2887

Funding

National Institutes of Health (NS40296)

J Troy Littleton

National Institutes of Health (MH104536)

J Troy Littleton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.