Glial Ca²⁺ Signaling and Seizure Susceptibility in Drosophila

Glial cells have been considered to play merely structural and supportive roles relative to the neuronal counterparts. Although many functions of glia within the brain have been identified, there is limited data on pathways by which glia acutely regulate neural activity. Mechanisms by which glia can regulate neuronal excitability include gliotransmission, neurotransmitter uptake and spatial K⁺ buffering. However, the molecular pathways mediating these processes are poorly characterized. Mammalian astrocytes, as well as other glial subtypes, were shown to exhibit complex and heterogeneous fluctuations in intracellular Ca²⁺. Growing evidence indicates that these dynamic Ca²⁺ signaling influences neuronal physiology on a rapid time scale: increased glial Ca²⁺ activity is associated with abnormal neuronal excitability, and pathologic elevation of glial Ca²⁺ can play an important role in the generation of seizures. Despite decades of studies on astrocytes, signaling pathways underlying these Ca²⁺ transients and their in vivo relevance to brain activity are poorly defined and controversial. The complex structure of astrocytes and the diversity of their interactions and contacts make it challenging to directly manipulate glial signaling only at specific domains. Drosophila glia provides an ideal system in this sense, as the central nervous system contains distinct glial subtypes that occupy distinct compartments in the brain and form relatively homogeneous interactions with other cellular counterparts, but still share many functional similarities with mammalian glial cells. Defining specific molecular components that underlie glial-neuronal communication will generate new mechanistic insights that will extend beyond our current understanding of glial contribution to epilepsy and neuronal dysfunction.