Increased expression of the astrocytic glutamate transporter GLT‐1 in the prefrontal cortex of schizophrenics

Abstract

To verify whether altered glial glutamate uptake contributes to the reduced efficacy of glutamatergic transmission reported in the prefrontal cortex of schizophrenics, we studied the expression of GLT-1, the transporter responsible for most glutamate transport, in autoptic samples of prefrontal cortex using real time quantitative RT-PCR, immunocytochemistry, and functional assays. GLT-1 mRNA levels in medication-free patients were 2.5-fold higher than in controls, whereas they were normal or reduced in patients treated with antipsychotics. We also observed a 4-fold increase in L-[ 3 H]-Glu uptake in Xenopus oocytes injected with mRNA from the prefrontal cortex of a medication-free schizophrenic and a 2-fold increase in GLT-1 protein in the same cortical area of another medication-free patient. Results suggest that GLT-1 mRNA, protein and function are increased in prefrontal cortex of schizophrenics. Following the demonstration that the psychotomimetic drug phencyclidine blocks NMDA subtypes of glutamate (Glu) receptors, several studies have provided evidence that in schizophrenics an altered function of NMDA receptors may reduce glutamatergic transmission in cortical circuits pivoting in the prefrontal cortex (Tsai and Coyle, 2002).Reduced neocortical glutamatergic signaling can also result from other mechanisms. Glu transporters are important regulators of excitatory transmission and are essential for maintaining physiological Glu levels (Conti and Weinberg, 1999;Danbolt, 2001); increased Glu uptake may thus reduce the efficacy of glutamatergic transmission. The possibility that increased Glu uptake plays a role in the pathophysiology of schizophrenia is suggested by the demonstration that in rat frontal cortex the antipsychotic clozapine reduces the expression and function of GLT-1-the plasma membrane transporter responsible for most Glu transport (Rothstein et al., 1996;Tanaka et al:, 1997)-in a strong and selective manner, thereby raising extracellular Glu levels (Melone et al., 2001(Melone et al., , 2003.We studied 25 samples from the prefrontal cortex (PFC) of 11 schizophrenics and 14 subjects without neurological or psychiatric diseases (hereinafter referred to as controls); 3 of the 11 schizophrenics had not received antipsychotic drugs for an amount of time sufficient to rule out their influence (Baldessarini and

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

“…Interestingly, synaptosomal liberation of glutamate was reduced in schizophrenic brain (Sherman et al 1991). An additional mechanistic basis for a reduction in extracellular glutamate levels was recently provided by an elegant study of Matute et al (2005). They showed that levels of both the mRNA and the protein for glial EAAT1 are elevated in the frontal cortex of schizophrenics and also that these transporters display a marked (fourfold) increase in functional activity.…”

Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia

“…A deficient uptake has been implicated in the pathogenesis of ischemic brain damage [Kuwahara et al, 1992] and may be involved in pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) [Rothstein et al, 1995]. Recently, significant increases of mRNA expression of EAAT1 in the thalamus, and EAAT2 in the thalamus and the prefrontal cortex have been reported in schizophrenics, suggesting a possibility that an excessive glutamate uptake is involved in schizophrenia [Smith et al, 2001;Matute et al, 2005]. This possibility was also suggested by the demonstration that the chronic treatment with antipsychotic clozapine reduces glutamate uptake mediated by GLT-1 (EAAT2) in the rat frontal cortex, thereby raising extracellular glutamate levels [Melone et al, 2001[Melone et al, , 2003].…”

Role of astrocytes in alterations of glutamatergic neurotransmission in schizophrenia

“…Однако при изуче-нии экспрессии мРНК для EAAT2 в префронтальной коре при шизофрении были получены достаточно противоре-чивые данные: как повышение экспрессии указанного транспортера [29,30], так и его снижение [31], а также от-сутствие достоверных изменений [32]. Однако большин-ство авторов полагают, что изменения собственно актив-ности астроцитарных переносчиков могут быть связаны с посттранскрипционным уровнем регуляции.…”