A central goal of neurobiology is to understand how the brain forms, stores, retrieves and encodes information and how these operations go awry in disease. The focus of this application is astrocytes, which make intimate contacts with neurons throughout the brain. Long considered simply the brain's glue, astrocytes are emerging as important regulators of neuronal function. Deciphering the roles of astrocytes in the brain is considered one of the major open questions in neuroscience. This Pioneer Award application seeks to test the novel hypothesis that an early step in brain disorders involves dysfunction of the very fine termini of astrocytes called branchlets that are known to abut synapses. In this context, we define dysfunction as branchlet withdrawal from synapses or altered branchlet signaling, including trophic support, to synapses. These dysfunctions would alter established astrocyte functions including neurotransmitter clearance, synapse regulation and maintenance. This in turn would alter the timing of synaptic transmission, contribute to excitotoxicity and perhaps trigger synapse removal. By focusing on the striatal microcircuitry, we will test the hypothesis that branchlets represents a hitherto overlooked mechanism in neurological and psychiatric disorders that could be exploited for novel therapeutics.

Public Health Relevance

We will study the physiology of astrocyte branchlets in the brain. Our data will provide new information to explore the roles of astrocytes in the normal healthy brain and in diseases of the nervous system, including the processes that lead to the development of neurological and psychiatric disorders. Our work is also highly relevant to all forms of brain damage. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: VERTEBRATE ANIMAL (Resume): ACCEPTABLE COMMITTEE BUDGET RECOMMENDATIONS: The bu

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1MH104069-03
Application #
8919456
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panchision, David M
Project Start
2013-09-26
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Yu, Xinzhu; Taylor, Anna M W; Nagai, Jun et al. (2018) Reducing Astrocyte Calcium Signaling In Vivo Alters Striatal Microcircuits and Causes Repetitive Behavior. Neuron 99:1170-1187.e9
Chai, Hua; Diaz-Castro, Blanca; Shigetomi, Eiji et al. (2017) Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence. Neuron 95:531-549.e9
Khakh, Baljit S; Beaumont, Vahri; Cachope, Roger et al. (2017) Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease. Trends Neurosci 40:422-437
Srinivasan, Rahul; Lu, Tsai-Yi; Chai, Hua et al. (2016) New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo. Neuron 92:1181-1195
Jiang, Ruotian; Diaz-Castro, Blanca; Looger, Loren L et al. (2016) Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice. J Neurosci 36:3453-70
Shigetomi, Eiji; Patel, Sandip; Khakh, Baljit S (2016) Probing the Complexities of Astrocyte Calcium Signaling. Trends Cell Biol 26:300-312
Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J et al. (2016) Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium. Front Neurosci 10:46
Anderson, Mark A; Burda, Joshua E; Ren, Yilong et al. (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195-200
Srinivasan, Rahul; Huang, Ben S; Venugopal, Sharmila et al. (2015) Ca(2+) signaling in astrocytes from Ip3r2(-/-) mice in brain slices and during startle responses in vivo. Nat Neurosci 18:708-17

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