Journal Article

Astroglial Glutamate Transporter Deficiency Increases Synaptic Excitability and Leads to Pathological Repetitive Behaviors in Mice

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

2015

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Animals / Animals, Newborn / Anxiety - genetics / Autism / Brain research / Cerebral Cortex - pathology / Cumulative Trauma Disorders - complications / Cumulative Trauma Disorders - drug therapy / Cumulative Trauma Disorders - genetics / Cumulative Trauma Disorders - pathology / Disease Models, Animal / Enzyme Inhibitors - therapeutic use / Excitatory Amino Acid Transporter 1 - deficiency / Excitatory Amino Acid Transporter 1 - genetics / Excitatory Amino Acid Transporter 2 - deficiency / Excitatory Amino Acid Transporter 2 - genetics / Excitatory Postsynaptic Potentials - genetics / Female / Gene Expression Regulation - genetics / Hyperalgesia - genetics / Male / Medical research / Mice / Mice, Transgenic / Nerve Degeneration - etiology / Nerve Degeneration - genetics / Nerve Tissue Proteins - metabolism / Neuroses / Obsessive compulsive disorder / Original / Pathogenesis / Proteins - genetics / Schizophrenia / Seizures - genetics / Stem cells / Synapses - genetics