Abstract
Abnormalities in L-glutamate signal transmission have been postulated to play a role in major mental illnesses. Recent studies suggest that glial glutamate transporters play critical roles in normal glutamatergic signal transmission. 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. Significant down-regulation of glial glutamate transporters, GLT1 and GLAST, in major depressive disorder has been reported. In the present study we examined the role of glial glutamate transporters in the pathogenesis of autism. Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction, communication deficits and repetitive and restricted patterns of behavior and interests. Yet, the etiology of autism is largely unknown. Aberrant glutamate function is often cited as an important element of risk for autism, but little is known about the underlying molecular determinants and neural mechanisms. In the present study, 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 and increased anxiety-like behavior. We observed enlarged amygdala and hippocampus. These mutant mice replicate many aspects of the behavioral and neuroanatomical abnormalities seen in autism. Scanning the genomes of autism spectrum disorder families revealed that GLT1 falls close to one of linkage peaks. Thus, these mutants are new animal models of autism. [J Physiol Sci. 2008;58 Suppl:S11]
