title: Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
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.
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Tomomi
authors: T
authors: Aida
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Junichi
authors: J
authors: Yoshida
authors: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Masatoshi
authors: M
authors: Nomura
authors: Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Asami
authors: A
authors: Tanimura
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yusuke
authors: Y
authors: Iino
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Miho
authors: M
authors: Soma
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Ning
authors: N
authors: Bai
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yukiko
authors: Y
authors: Ito
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Wanpeng
authors: W
authors: Cui
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Hidenori
authors: H
authors: Aizawa
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Michiko
authors: M
authors: Yanagisawa
authors: Laboratory for Neuron-Glia Circuitry, Brain Science Institute, RIKEN, Saitama, Japan.
authors: Terumi
authors: T
authors: Nagai
authors: Laboratory for Neuron-Glia Circuitry, Brain Science Institute, RIKEN, Saitama, Japan.
authors: Norio
authors: N
authors: Takata
authors: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
authors: Kenji F
authors: KF
authors: Tanaka
authors: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Ryoichi
authors: R
authors: Takayanagi
authors: Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Masanobu
authors: M
authors: Kano
authors: Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Munich, Germany.
authors: Magdalena
authors: M
authors: Götz
authors: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
authors: Hajime
authors: H
authors: Hirase
authors: 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.
authors: Kohichi
authors: K
authors: Tanaka
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology*; D012090:Cumulative Trauma Disorders / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D027341:Excitatory Amino Acid Transporter 1 / Q000172:deficiency* / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2 / Q000172:deficiency* / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006930:Hyperalgesia / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012640:Seizures / Q000235:genetics; D013569:Synapses / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D009419:Nerve Tissue Proteins; D011506:Proteins; C472408:ROSA22 protein, mouse; C493396:Slc1a2 protein, mouse