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Neuropsychopharmacology. 2015 Jun;40(7):1569-79. doi: 10.1038/npp.2015.26. Epub 2015 Feb 9.

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

Author information

1
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
2
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
3
Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
4
Laboratory for Neuron-Glia Circuitry, Brain Science Institute, RIKEN, Saitama, Japan.
5
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
6
Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Munich, Germany.
7
1] Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan [2] JST, CREST, Saitama, Japan [3] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.

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 (GLAST(CreERT2/+)/GLT1(flox/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.

PMID:
25662838
PMCID:
PMC4915262
DOI:
10.1038/npp.2015.26
[Indexed for MEDLINE]
Free PMC Article

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