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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anxiety / genetics
  • 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
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / etiology
  • Nerve Degeneration / genetics
  • Nerve Tissue Proteins / metabolism
  • Proteins / genetics
  • Seizures / genetics
  • Synapses / genetics*

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 2
  • Nerve Tissue Proteins
  • Proteins
  • ROSA22 protein, mouse
  • Slc1a2 protein, mouse