Mounting evidence suggests that neurons and glia engage in bi-directional signaling that affects the function and development of neural circuits. Glia can influence the excitability of neurons, by controlling the amount of neurotransmitters in the extrasynaptic space, and can directly modulate synaptic transmission. In addition, glia are the central regulators of the neurovascular interactions that control neuronal metabolism. To better understand glial function, it is essential to unravel how the close interaction between neurons and glia is established during development and the effect this has on the stabilization of neural circuits. This proposal describes an approach to elucidate the role of neuron-glia signaling in the development of murine retinal circuits. The proposed investigations will provide the basis for a long-term research program dedicated to exploring how the precise signaling between neurons, glia, and blood vessels is established and maintained. M?ller glia are the last cell type to proliferate in the retina, and must integrate into an existing immature circuit duringa period of spontaneous correlated activity called retinal waves. Shortly before eye opening, retinal waves are mediated by glutamatergic signaling and are thought to propagate by glutamate spillover into the extrasynaptic space. M?ller cells mature in morphology and function during glutamatergic waves, and may stabilize retinal circuits when waves cease and vision begins. Two forms of neuron-glia signaling are explored in this proposal. In the first aim, we will determine how the maturation of glial cell transporter function affects the development of neuronal circuits. In the second aim, we will investigate how spontaneous and evoked neuronal activity influences glial calcium signaling.
In aim 1 we will use optical and electrophysiological methods to describe the maturation of M?ller cell transporter function. Levels of glutamate can be directly observed with glutamate optical sensors that increase in fluorescence when glutamate binds. I will use these sensors to monitor extrasynaptic glutamate during the transition from retinal waves to vision, and to ascertain whether or not glutamate spillover reaches M?ller cells. M?ller transporters will be blocked pharmacologically and two-photon calcium imaging of neuronal populations will be used to assess the effect on retinal circuits.
In aim 2 we will use transgenic mice expressing the calcium indicator GCaMP3 in M?ller cells to investigate whether neural activity drives M?ller calcium transients throughout retinal development. An understanding of how glial cells change neuronal function as they integrate into maturing circuits will lead to fundamental insights about the cellular and molecular mechanisms of neuron-glia signaling. The maintenance of neuron-glia interactions is vital for the health of the nervous system, and in particular, the glial transporter function has proven clinical significance.

Public Health Relevance

Glial regulation of neuronal activity has profound significance for human health. In particular, glial cell transporters are necessary to prevent the imbalance of excitation and inhibition commonly observed in pathophysiological states, including migraine, Alzheimer's Disease, schizophrenia, and epilepsy. The investigations of neuron-glia interactions proposed here will provide insights into how the precise signaling between neurons and glia is established during development and maintained into adulthood.

National Institute of Health (NIH)
National Eye Institute (NEI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F03A-N (20))
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Agarwal, Neeraj
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University of California Berkeley
Schools of Arts and Sciences
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Rosa, Juliana M; Bos, RĂ©mi; Sack, Georgeann S et al. (2015) Neuron-glia signaling in developing retina mediated by neurotransmitter spillover. Elife 4: