Cognitive dysfunction and glutamate reuptake: effect of EAAT2 polymorphism in schizophrenia

A disturbance of glutamatergic transmission has been suggested to contribute tothe development of schizophrenic pathophysiology, based primarily on the ability of glutamate receptor antagonists to induce schizophrenic-like symptoms. Theexcitatory amino acid transporter 2 (EAAT2) is responsible for the majority ofglutamate uptake. It also contributes to energy metabolism in the brain, bytransporting glutamate into astrocytes for conversion into glutamine. Adysregulation of its level of expression has been associated with multipleneurological disorders. Blocking glutamate uptake by EAAT2 in culturedoligodendrocytes leads to cell death, demyelination and axonal damage, suggestingthat it is crucial for normal oligodendrocyte function. Different studies focusedon EAAT2 alterations among subjects affected by schizophrenia, reporting adecreased expression in the parahippocampal region and in the dorsolateralprefrontal cortex. Moreover, subjects with the high-risk metabotropic glutamatereceptor 3 (GRM3) haplotype associated with schizophrenia had lower EAAT2expression in the prefrontal cortex and also showed impaired cognitiveperformances for measures of verbal list learning and verbal fluency. EAAT2protein activity is regulated by a SNP rs4354668 (-181T/G) which falls in thegene promoter region, with the G allele resulting in a lower activity of thetransporter. Based on these data, we assessed possible effects of the -181T/GEAAT2 polymorphism on two core prefrontal cognitive performances, known to beimpaired in schizophrenia, in a sample of 211 clinically stabilized patients. We observed better executive functions (WCST, no. of categories) and working memory (N-back: 1-back, 2-back) performances in subjects homozygous for the T allele,compared to the G carriers group. These observations suggest that the presence ofthe G allele is associated, among patients with schizophrenia, with adisadvantageous effect on core cognitive functions that depend on prefrontalcortex activity. These results are preliminary and need to be replicated byfuture and larger studies, however they suggest that EAAT2 inefficiency mayrepresent a target of interest for development of pharmacological strategiesaimed to improve prefrontal performances by compensating the impaired glutamatereuptake.