@article{7e12bf139b9d4b3cb42970b466cebf38,
title = "Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue",
abstract = "Hyperactivity and disturbances of attention are common behavioral disorders whose underlying cellular and neural circuit causes are not understood. We report the discovery that striatal astrocytes drive such phenotypes through a hitherto unknown synaptic mechanism. We found that striatal medium spiny neurons (MSNs) triggered astrocyte signaling via γ-aminobutyric acid B (GABAB) receptors. Selective chemogenetic activation of this pathway in striatal astrocytes in vivo resulted in acute behavioral hyperactivity and disrupted attention. Such responses also resulted in upregulation of the synaptogenic cue thrombospondin-1 (TSP1) in astrocytes, increased excitatory synapses, enhanced corticostriatal synaptic transmission, and increased MSN action potential firing in vivo. All of these changes were reversed by blocking TSP1 effects. Our data identify a form of bidirectional neuron-astrocyte communication and demonstrate that acute reactivation of a single latent astrocyte synaptogenic cue alters striatal circuits controlling behavior, revealing astrocytes and the TSP1 pathway as therapeutic targets in hyperactivity, attention deficit, and related psychiatric disorders. Bi-directional communication between striatal neurons and astrocytes drives acute behavioral hyperactivity and disrupted attention.",
keywords = "astrocyte, attention deficit, behavior, calcium, gabapentin, hyperactivity, microcircuit, striatum, thrombospondin",
author = "Jun Nagai and Rajbhandari, {Abha K.} and Gangwani, {Mohitkumar R.} and Ayaka Hachisuka and Giovanni Coppola and Masmanidis, {Sotiris C.} and Fanselow, {Michael S.} and Khakh, {Baljit S.}",
note = "Funding Information: This work was supported by NIH grants NS060677 and MH104069 (to B.S.K.). B.S.K. was also supported by the Ressler Family Foundation. J.N. was partly supported by JSPS overseas research fellowship H28-729 and Uehara Memorial Foundation (Japan) overseas postdoctoral research fellowship 201730082. We acknowledge support from the NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691 to G.C.) and the Genetics, Genomics and Informatics Core of the Semel Institute of Neuroscience at UCLA (U54HD087101-01 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development). A.K.R. and M.S.F. were supported by RO1 MH062122, NARSAD 26612 (to A.K.R.) and the Staglin Center for Brain and Behavioral Health. Behavioral experiments utilized the UCLA Behavioral Testing Core. A.H. and S.C.M. were supported NIH grants NS100050 and DA042739 and NSF NeuroNex Technology Hub award 1707408. We thank the UCLA Neuroscience Genomics Core (https://www.semel.ucla.edu/ungc) for assistance with sequencing and Fuying Gao for help with RNA-seq data analysis. We also thank Michael V. Sofroniew and Christopher J. Evans for sharing equipment and Drs. Yu, Beaumont, Munoz-Sanjuan, Flint, and Sofroniew for valuable comments and discussions. J.N. performed most of the experiments. M.R.G. performed the in vivo optical stimulation experiments and helped with immunohistochemistry. A.K.R. helped with the behavior experiments. A.H. and S.C.M. helped with in vivo electrophysiology and provided equipment. G.C. provided guidance on the analysis of RNA-seq data. M.S.F. supervised the behavioral experiments. J.N. and B.S.K. analyzed data and assembled the figures. B.S.K. conceived and directed the project. B.S.K. and J.N. wrote the paper with help from M.S.F. All authors contributed. The authors declare no competing interests. Funding Information: This work was supported by NIH grants NS060677 and MH104069 (to B.S.K.). B.S.K. was also supported by the Ressler Family Foundation. J.N. was partly supported by JSPS overseas research fellowship H28-729 and Uehara Memorial Foundation (Japan) overseas postdoctoral research fellowship 201730082 . We acknowledge support from the NINDS Informatics Center for Neurogenetics and Neurogenomics ( P30 NS062691 to G.C.) and the Genetics, Genomics and Informatics Core of the Semel Institute of Neuroscience at UCLA ( U54HD087101-01 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development ). A.K.R. and M.S.F. were supported by RO1 MH062122 , NARSAD 26612 (to A.K.R.) and the Staglin Center for Brain and Behavioral Health . Behavioral experiments utilized the UCLA Behavioral Testing Core. A.H. and S.C.M. were supported NIH grants NS100050 and DA042739 and NSF NeuroNex Technology Hub award 1707408 . We thank the UCLA Neuroscience Genomics Core ( https://www.semel.ucla.edu/ungc ) for assistance with sequencing and Fuying Gao for help with RNA-seq data analysis. We also thank Michael V. Sofroniew and Christopher J. Evans for sharing equipment and Drs. Yu, Beaumont, Munoz-Sanjuan, Flint, and Sofroniew for valuable comments and discussions. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "16",
doi = "10.1016/j.cell.2019.03.019",
language = "English",
volume = "177",
pages = "1280--1292.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}