Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice

Tomomi Aida, Junichi Yoshida, Masatoshi Nomura, Asami Tanimura, Yusuke Iino, Miho Soma, Ning Bai, Yukiko Ito, Wanpeng Cui, Hidenori Aizawa, Michiko Yanagisawa, Terumi Nagai, Norio Takata, Kenji Tanaka, Ryoichi Takayanagi, Masanobu Kano, Magdalena Götz, Hajime Hirase, Kohichi Tanaka

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLASTCreERT2/+ /GLT1flox/flox, iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.

Original languageEnglish
Pages (from-to)1569-1579
Number of pages11
JournalNeuropsychopharmacology
Volume40
Issue number7
DOIs
Publication statusPublished - 2015 Feb 4

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Amino Acid Transport System X-AG
Astrocytes
Synapses
Memantine
Tics
Tourette Syndrome
Grooming
Premature Mortality
Obsessive-Compulsive Disorder
N-Methyl-D-Aspartate Receptors
Neuroglia
Seizures
Head
Neurons

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice. / Aida, Tomomi; Yoshida, Junichi; Nomura, Masatoshi; Tanimura, Asami; Iino, Yusuke; Soma, Miho; Bai, Ning; Ito, Yukiko; Cui, Wanpeng; Aizawa, Hidenori; Yanagisawa, Michiko; Nagai, Terumi; Takata, Norio; Tanaka, Kenji; Takayanagi, Ryoichi; Kano, Masanobu; Götz, Magdalena; Hirase, Hajime; Tanaka, Kohichi.

In: Neuropsychopharmacology, Vol. 40, No. 7, 04.02.2015, p. 1569-1579.

Research output: Contribution to journalArticle

Aida, T, Yoshida, J, Nomura, M, Tanimura, A, Iino, Y, Soma, M, Bai, N, Ito, Y, Cui, W, Aizawa, H, Yanagisawa, M, Nagai, T, Takata, N, Tanaka, K, Takayanagi, R, Kano, M, Götz, M, Hirase, H & Tanaka, K 2015, 'Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice', Neuropsychopharmacology, vol. 40, no. 7, pp. 1569-1579. https://doi.org/10.1038/npp.2015.26
Aida, Tomomi ; Yoshida, Junichi ; Nomura, Masatoshi ; Tanimura, Asami ; Iino, Yusuke ; Soma, Miho ; Bai, Ning ; Ito, Yukiko ; Cui, Wanpeng ; Aizawa, Hidenori ; Yanagisawa, Michiko ; Nagai, Terumi ; Takata, Norio ; Tanaka, Kenji ; Takayanagi, Ryoichi ; Kano, Masanobu ; Götz, Magdalena ; Hirase, Hajime ; Tanaka, Kohichi. / Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice. In: Neuropsychopharmacology. 2015 ; Vol. 40, No. 7. pp. 1569-1579.
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