Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue

  • Cell. 2019 May 16;177(5):1280-1292.e20. doi: 10.1016/j.cell.2019.03.019.
Jun Nagai  1 ,  Abha K Rajbhandari  2 ,  Mohitkumar R Gangwani  1 ,  Ayaka Hachisuka  3 ,  Giovanni Coppola  4 ,  Sotiris C Masmanidis  3 ,  Michael S Fanselow  5 ,  Baljit S Khakh  6
Affiliations
  • 1. Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
  • 2. Department of Psychology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
  • 3. Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
  • 4. Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
  • 5. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Psychology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
  • 6. Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA. Electronic address: [email protected].
PMID: 31031006 DOI: 10.1016/j.cell.2019.03.019
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.

Keywords
astrocyte; attention deficit; behavior; calcium; gabapentin; hyperactivity; microcircuit; striatum; thrombospondin.
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