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Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue

Author:
Nagai, Jun, Rajbhandari, Abha K., Gangwani, Mohitkumar R., Hachisuka, Ayaka, Coppola, Giovanni, Masmanidis, Sotiris C., Fanselow, Michael S., Khakh, Baljit S.
Source:
Cell 2019 v.177 no.5 pp. 1280-1292.e20
ISSN:
0092-8674
Subject:
action potentials, astrocytes, behavior disorders, gamma-aminobutyric acid, gamma-aminobutyric acid receptors, neurons, phenotype, synapse, synaptic transmission, therapeutics
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.
Agid:
6441436