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

Marco Spangaro, Marta Bosia, Andrea Zanoletti, Margherita Bechi, Federica Cocchi, Adele Pirovano, Cristina Lorenzi, Placido Bramanti, Francesco Benedetti, Enrico Smeraldi, Roberto Cavallaro

Research output: Contribution to journalArticlepeer-review


A disturbance of glutamatergic transmission has been suggested to contribute to the development of schizophrenic pathophysiology, based primarily on the ability of glutamate receptor antagonists to induce schizophrenic-like symptoms. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake. It also contributes to energy metabolism in the brain, by transporting glutamate into astrocytes for conversion into glutamine. A dysregulation of its level of expression has been associated with multiple neurological disorders. Blocking glutamate uptake by EAAT2 in cultured oligodendrocytes leads to cell death, demyelination and axonal damage, suggesting that it is crucial for normal oligodendrocyte function. Different studies focused on EAAT2 alterations among subjects affected by schizophrenia, reporting a decreased expression in the parahippocampal region and in the dorsolateral prefrontal cortex. Moreover, subjects with the high-risk metabotropic glutamate receptor 3 (GRM3) haplotype associated with schizophrenia had lower EAAT2 expression in the prefrontal cortex and also showed impaired cognitive performances for measures of verbal list learning and verbal fluency. EAAT2 protein activity is regulated by a SNP rs4354668 (-181. T/G) which falls in the gene promoter region, with the G allele resulting in a lower activity of the transporter. Based on these data, we assessed possible effects of the -181. T/G EAAT2 polymorphism on two core prefrontal cognitive performances, known to be impaired 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 of the G allele is associated, among patients with schizophrenia, with a disadvantageous effect on core cognitive functions that depend on prefrontal cortex activity. These results are preliminary and need to be replicated by future and larger studies, however they suggest that EAAT2 inefficiency may represent a target of interest for development of pharmacological strategies aimed to improve prefrontal performances by compensating the impaired glutamate reuptake.

Original languageEnglish
Pages (from-to)151-155
Number of pages5
JournalNeuroscience Letters
Issue number2
Publication statusPublished - Aug 1 2012


  • Cognitive deficit
  • Excitatory amino acid transporter 2 (EAAT2)
  • Executive functions
  • Glutamate uptake
  • Schizophrenia
  • Working Memory

ASJC Scopus subject areas

  • Neuroscience(all)


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