Letter to the editor Genetic variability of glutamate reuptake: Effect on white matter integrity and working memory in schizophrenia Elena Mazza b,1 , Marco Spangaro a,b, ⁎ ,1 , Sara Poletti b , Roberto Cavallaro a,b , Francesco Benedetti a,b a IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy b Vita-Salute San Raffaele University, Milan, Italy article info Article history: Received 30 January 2019 Received in revised form 26 February 2019 Accepted 3 March 2019 Available online xxxx Keywords: Schizophrenia EAAT2 Glutamate reuptake White matter Working memory Cognitive deficit Working memory (WM) deficit is a core feature of schizophrenia, as- sociated with impairments in overall cognitive functioning, functional outcome, and course of illness (Lett et al., 2014). Glutamate is the major central neurotransmitter, and alterations of its regulation mecha- nisms have been largely associated with cognitive and structural im- pairments in schizophrenia (Moghaddam and Javitt, 2012). The excitatory amino acid transporter 2 (EAAT2), is responsible for N90% of glutamate uptake, playing a crucial role preventing excitoxic damage, modulating synaptic activity and contributing to preserve an efficient energy metabolism. A functional SNP located in the gene promoter, rs4354668 (-181 T/G), modulates EAAT2 expression, influencing both cerebral activity and structure (Mallolas et al., 2006; Zhang et al., 2015). We previously reported that patients with schizophrenia carry- ing the G allele, associated with lower EAAT2 expression, show im- paired WM performance and reduced WM improvements after cognitive rehabilitation therapy (Spangaro et al., 2014, 2018a). More- over, we also observed reduced frontal cortical volumes among EAAT2 Schizophrenia Research xxx (xxxx) xxx ⁎ Corresponding author at: Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Stamira d'Ancona 20, 20127 Milano, Italy. E-mail address: spangaro.marco@hsr.it (M. Spangaro). 1 These authors contributed equally to this work.. SCHRES-08246; No of Pages 3 G carriers, associated with poor WM performance, thus hypothesizing the presence of an underling excitoxic process (Poletti et al., 2014). In order to further investigate the relationship between EAAT2 genetic variability, cognition and brain structure in schizophrenia, in the pres- ent study we aimed to investigate possible effect of rs4354668 on white matter integrity, as well as possible association of Diffusion Ten- sor Imaging (DTI) measures with WM performance. The study included 39 clinically stabilized patients (26 males and 13 females) with a diagnosis of schizophrenia (DSM-IV-TR criteria). Exclu- sion criteria were: age N 65 years, intellectual disability, psychiatric co- morbidities, substance abuse, neurological disorders. All subjects provided informed consent to a protocol approved by the local Ethical Committee following the principles of the Declaration of Helsinki. WM performance was evaluated with the N-Back test (Callicott et al., 2003). For genotyping and DTI acquisition/analysis technical details please see our previous works (Spangaro et al., 2018a,b). Analysis of covariance (ANCOVA) was used to evaluate differences in WM between genotype groups considering N-Back results as depen- dent variables, EAAT2 genotype as categorical factor and age as covari- ate. Consistently with literature, we grouped subjects homozygous for the T allele (19 subjects) vs. G carriers (22 subjects). A t-test on DTI measures of white matter microstructure across the white matter skeleton was performed between genotype groups. We then performed an interaction analysis between genotype and WM, and post hoc analyses to evaluate effect direction. We accounted for the effects of nuisance covariates potentially influencing white matter structure: age, sex, onset, and antipsychotics dosage (chlorpromazine equivalents). T/T patients showed better WM performances (ANCOVA; 1-back: F = 6.30, p = .017; 2-back: F = 4.86, p = .034) and a widespread higher white matter integrity, as indicated by the observation of lower Axial Diffusivity (AD), Mean Diffusivity (MD), and Radial Diffusivity (RD) in different areas including internal capsule, corpus callosum, bilateral su- perior longitudinal fasciculus, anterior thalamic radiation, cingulum, corticospinal tract and anterior/superior corona radiate. Moreover, white matter integrity differently associated with WM performances between genotype groups, with a positive correlation be- tween 2-back and Fractional Anisotropy (FA) and a negative correlation https://doi.org/10.1016/j.schres.2019.03.004 0920-9964/© 2019 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: E. Mazza, M. Spangaro, S. Poletti, et al., Genetic variability of glutamate reuptake: Effect on white matter integrity and working memory in schizophrenia, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.03.004