Abstract
Abnormalities in L-glutamate signal transmission have been postulated to play a role in major mental illnesses. The glial disruption results in decreased uptake of glutamate and an elevation of extracellular glutamate levels. Elevated extracellular glutamate may cause cytotoxic damage to neurons and glia. Rare variants and down-regulation of glial glutamate transporters, GLT1 and GLAST, in psychiatric disorders has been reported. In the present study we examined the role of glial glutamate transporters in the pathogenesis of major metal illnesses including schizophrenia, depression, obsessive -compulsive disorders and autism. We generated animal models in which glutamate receptors are overstimulated by genetic down-regulation of glial glutamate transporters. Resulting mutant mice showed abnormal social interaction, increased anxiety-like behavior, physical tics and compulsive grooming behavior and select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia. These mutant mice replicate many aspects of the behavioral and neuroanatomical abnormalities seen in major mental illnesses. Thus, these mutants are new animal models of major mental illness. Therefore, augmentation of glial glutamate transporter activity may be a novel strategy for the management of major mental illnesses.
