Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia

Abstract

Glutamate transporters facilitate the buffering, clearance and cycling of glutmate and play an important role in maintaining synaptic and extrasynaptic glutamate levels. Alterations in glutamate transporter expression may lead to abnormal glutamate neurotransmission contributing to the pathophysiology of schizophrenia. In addition, alterations in the architecture of the superior temporal gyrus and hippocampus have been implicated in this illness, suggesting that synapses in these regions may be remodeled from a lifetime of severe mental illness and antipsychotic treatment. Thus, we hypothesize that glutamate neurotransmission may be abnormal in the superior temporal gyrus and hippocampus in schizophrenia. To test this hypothesis, we examined protein expression of excitatory amino acid transporter 1-3 and vesicular glutamate transporter 1 and 2 in subjects with schizophrenia (n = 23) and a comparison group (n = 27). We found decreased expression of EAAT1 and EAAT2 protein in the superior temporal gyrus, and decreased EAAT2 protein in the hippocampus in schizophrenia. We didn’t find any changes in expression of the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. In addition, we did not detect an effect of antipsychotic medication on expression of EAAT1 and EAAT2 proteins in the temporal association cortex or hippocampus in rats treated with haloperidol for 9 months. Our findings suggest that buffering and reuptake, but not presynaptic release, of glutamate is altered in glutamate synapses in the temporal lobe in schizophrenia.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Most importantly, the EAAT genes have promoter regions that are responsive to immune regulation through intracellular immune signaling molecules such as the transcription factor NF-kB (Zou and Crews, 2005). EAAT proteins are synthesized in the endoplasmic reticulum and appear to undergo extensive posttranslational modification in the Golgi apparatus (Kalandadze et al, 2004) before being trafficked onto the plasma membrane for surface expression (Conradt and Stoffel, 1997;Figiel and Dzwonek, 2007;Gamboa and Ortega, 2002;Schluter et al, 2002;Shan et al, 2013). The surface EAATs are periodically removed from the plasma membrane via endocytosis, and are then either shuttled back to the cell surface (via recycling endosomes) or targeted for degradation in lysosomes (Nakagawa et al, 2008).…”

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness

“…Furthermore, SLC1A2 and SLC1A3 protein were found to be reduced in mGluR2-/-and mGluR3-/-mice, which might be lead to, altered synaptic glutamate levels . Recent literature also indicates altered expression of glutamate transporters-SLC1A1, SLC1A2, SLC1A3, and SLC1A4 resulting in the abnormal glutamate neurotransmission which have all been implicated in several pathological conditions including schizophrenia [Bianchi et al, 2001;Smith et al, 2001;Weis et al, 2007;Bauer et al, 2010;Shan et al, 2013;Wilmsdorff et al, 2013]. Thus, genetic variations in these genes also need to be studied to assess their potential to influence the disease development and therapeutic outcome.…”

Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons?

“…31 Some cases of ALS have as high as a 90% decrease in region-level expression of EAAT2 protein, while region-level decreases of EAAT2 protein expression in the superior temporal gyrus, hippocampus and thalamus in schizophrenia are more modest, in the 20-30% range. 37 The authors of these ALS studies speculate that diminished glutamate reuptake increases inward calcium currents in postsynaptic neurons, initiating excitotoxic events including dissociation of mitochondrial proteins. 31 Recent findings may support this hypothesis.…”

“…We previously reported diminished EAAT1 protein levels in the frontal cortex and superior temporal gyrus in schizophrenia. 37,55,56 EAAT1 and EAAT2 expression is generally found in nonoverlapping subsets of glia, suggesting that changes in EAAT1 expression are in a functionally discrete subset of cells that do not express EAAT2. 57 Glutamate aspartate transporter (GLAST; rodent EAAT1) knockout mice have behavioral endophenotypes associated with schizophrenia, including deficits in working memory and acoustic startle, without a decrease in EAAT2 expression.…”