Astrocytes extend highly branched processes that ensheath excitatory synapses, providing a barrier to diffusion and the means to localize transporters near sites of release. This "tripartite" structure, consisting of presynaptic and postsynaptic elements and associated astrocyte processes, limits interactions between densely packed synapses, and allows astrocytes to modulate synaptic signaling through the release of neuroactive molecules (gliotransmitters) in response to a rise in intracellular Ca2-H. Despite the many in vitro studies that have implicated astrocytes in synaptic plasticity, our knowledge about their roles in synaptic modulation in vivo is limited, in part, due to difficulties associated with monitoring and manipulating astrocyte activity in the intact CNS. Due to its uniform structure and accessibility, the cerebellar cortex offers many advantages for analyzing neuron-astrocyte interactions. This proposal will use in vivo two photon imaging, in combination with newly developed transgenic mice that allow cell-specific expression of genetically encoded Ca2-H indicators, to monitor Bergmann glia activity in response to voluntary movement. The mechanisms responsible for initiating these events, such as activation of Ca2+ permeable AMPA receptors, will be evaluated by selective disruption of AMPA receptor signaling in Bergmann glia. A further goal of these studies is to investigate the involvement of the Ca2-H release-activated Ca2-H (CRAC) channel complex in generating these transients, by genetically deleting Orail and STIM1 from Bergmann glia. The effects of disruption of this robust form of signaling on motor coordination will be evaluated to assess the broader consequence of Ca2+ signaling in these glial cells. These studies will serve as a crucial template with which to understand the role of astrocytes in modulating excitatory synapses in other brain regions relevant for mental health.

Public Health Relevance

Astroglial cells in the cerebellar cortex exhibit widespread activity in response to voluntary movement; however, the role of this activity is unknown. This proposal will determine how this activity is initiated and how it influences the ability of the cerebellum to coordinate movements. Identification of new pathways for modulating neural activity in the cerebellum could lead to new approaches for treating movement disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-L)
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Johns Hopkins University
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Paukert, Martin; Agarwal, Amit; Cha, Jaepyeong et al. (2014) Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82:1263-70
Agarwal, Amit; Bergles, Dwight E (2014) Astrocyte morphology is controlled by neuron-derived FGF. Neuron 83:255-7