Dataset Information

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 ?-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.

SUBMITTER: Nagai J

PROVIDER: S-EPMC6526045 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue.

Nagai Jun J Rajbhandari Abha K AK Gangwani Mohitkumar R MR Hachisuka Ayaka A Coppola Giovanni G Masmanidis Sotiris C SC Fanselow Michael S MS Khakh Baljit S BS

Cell 20190425 5

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 (GABA<sub>B</sub>) receptors. Selective chemogenetic activation of this pathway in striatal astrocytes in vivo resulted in acut ...[more]

PMID: 31031006

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Project description:OBJECTIVES:Executive function (EF) deficits are major impairments in adults with attention deficit/hyperactivity disorder (ADHD). Previous studies have shown that the insula is involved in cognitive and EFs. However, the insula is highly heterogeneous in function, and few studies have focused on functional networks which related to specific insular subregions in adults with ADHD. We explored the functional networks of the insular subregions [anterior insula (AI), mid-insula (MI), and posterior insula (PI)]. Furthermore, their correlations with self-ratings of ecological EFs, including inhibition, shifting, and working memory were investigated. METHODS:Resting-state functional magnetic resonance imaging data in 28 adults with ADHD and 30 matched healthy controls (HCs) were analyzed. The seed-based resting-state functional connectivity (RSFC) of the insular subregions was evaluated. We also investigated their associations with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) inhibition, working memory, and shifting factor scores. RESULTS:Compared with HCs, adults with ADHD showed altered RSFC of the AI, with the precuneus, precentral gyrus, and inferior temporal gyrus extended to the middle temporal gyrus, lingual gyrus, and superior occipital gyrus, respectively. There were no significant differences in RSFC of the MI and PI between the two groups. Within the HC group, working memory scores were associated with the RSFC of AI with precuneus and temporal gyrus. However, there was no correlation between these variables in the ADHD group. CONCLUSION:The study evaluated RSFC patterns of the insular subregions in adults with ADHD for the first time. Altered RSFC of the AI which is a crucial region of salience network (SN) and part of regions in default mode network (DMN), were detected in adults with ADHD in both results with and without global signal regression (GSR), suggesting that disrupted SN-DMN functional connectivity may be involved in EF impairments in adults with ADHD, especially with respect to working memory. Deficits of the AI which is involved in salient stimuli allocation, might be associated with the pathophysiology of ADHD. The inconsistent results of MI and PI between analyses with and without GSR need further exploration.

Dataset Information

Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue.

Publications

Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue.

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