The long-term goal of the proposed research is to reveal how electrically non-excitable glial cells support synaptic transmission under the control of neurons using visual system as a model. As previous studies on vision mostly have been focused on the visual transduction cascades and the neuronal circuits, our knowledge about the role of glial cells in vision is still very limited. It is well established that visual glial cells are known for their functions in neuron protection, structural maintenance and control of environmental K+ and neurotransmitter levels. But neurobiological research in the last decade has found that, in addition to supportive roles, the central neuropil glia astrocytes can respond to various neurotransmitters, thus they may actively modulate neuronal synaptic transmissions. Neurotransmitter receptors are also detected in visual glia including Mller cells. However, it remains to be elucidated on how glia support signal transmission in visual system, and how this glial function is regulated conversely by neurons. We are proposing to use the Drosophila visual system as a novel, genetic model to study this function of perisynaptic glia, which allows the observation of neuronal activities in live animals after signaling molecules are genetically manipulated in either glia or neuron. In the first visual neuropil region (lamina) of fly, photoreceptor axons release histamine upon light stimulation to hyperpolarize projective large monopolar cells (LMC). All neuronal processes are wrapped laterally by three epithelial glia cells (EG) in each laminar cartridge. We have previous found that EG concentrate a glutamate-gated chloride channel GluCl in special membrane processes abutting terminals of T1 interneuron. In our preliminary study, loss of GluCl diminished the Ca2+ response of LMC to light change, and impaired fly locomotion vision in dim conditions. Both dark-vision and electroretinogram defects of the GluCl mutant were phenocopied by downregulation of a glutamate transporter EAAT1 in T1, suggesting the involvement of T1 neuron and EAAT1 in the stimulation of GluCl. In addition, a cation channel NA in T1 appeared to function upstream of GluCl as well. Based on these observations, we propose to test a voltage-dependent, non-vesicular mechanism of neuron-glia communication, in which T1 neuron releases glutamate through EAAT1 to open a GluCl-gated Cl- pool in EG, and thereby facilitate the inhibition of LMC by photoreceptors. This model may represent a general mechanism for interneuron to modulate synaptic weight through glia in both fly and mammals. Using a combination of molecular and cell biological, genetic, histological, electrophysiological and in vivo imaging approaches, we will 1. Test the hypothesis that a GluCl-gated glial Cl- pool is essential for the inhibitory visual; 2. Test the hypothesis that T1 neuron releases glutamate through EAAT1 to open glial GluCl channel; 3. Test the hypothesis that depolarization of T1 is required for EAAT1 to release glutamate.
Glial cells support neuronal function and survival in both physiological and pathological conditions. In this proposal we plan to use the Drosophila visual sytem as a genetic model to study how glial cells directly modulate neuronal synaptic transmission and how this glial function is conversely controlled by neurons. Findings from this study will reveal novel, general mechanisms of neuron-glia interaction, and help to advance pathological understanding of retinopathies and psychiatric disorders.
| Chaturvedi, Ratna; Luan, Zhuo; Guo, Peiyi et al. (2016) Drosophila Vision Depends on Carcinine Uptake by an Organic Cation Transporter. Cell Rep 14:2076-2083 |
| Luan, Zhuo; Quigley, Caitlin; Li, Hong-Sheng (2015) The putative Na?/Cl?-dependent neurotransmitter/osmolyte transporter inebriated in the Drosophila hindgut is essential for the maintenance of systemic water homeostasis. Sci Rep 5:7993 |
| Luan, Zhuo; Reddig, Keith; Li, Hong-Sheng (2014) Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration. Exp Neurol 261:791-801 |
| Chaturvedi, Ratna; Reddig, Keith; Li, Hong-Sheng (2014) Long-distance mechanism of neurotransmitter recycling mediated by glial network facilitates visual function in Drosophila. Proc Natl Acad Sci U S A 111:2812-7 |
| Luan, Zhuo; Li, Hong-Sheng (2012) Inwardly rectifying potassium channels in Drosophila. Sheng Li Xue Bao 64:515-9 |
