Expression of excitatory amino acid transporter interacting protein transcripts in the thalamus in schizophrenia

Abstract

The excitatory amino acid transporters (EAATs) are a family of plasma membrane proteins that maintain synaptic glutamate concentration by removing glutamate from the synaptic cleft. EAATs are expressed by glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4) throughout the brain. Glutamate reuptake is regulated, in part, by EAAT-interacting proteins that modulate subcellular localization and glutamate transport activity of the EAATs. Several lines of investigation support the hypothesis of glutamatergic abnormalities in schizophrenia. Previous work in our laboratory demonstrated increased expression of EAAT1 and EAAT2 transcripts in the thalamus, suggesting that alterations in synaptic glutamate levels may contribute to the pathophysiology of schizophrenia. Since EAAT-interacting proteins regulate EAAT function, directly impacting glutamatergic neurotransmission, we hypothesized that expression of EAAT-interacting proteins may also be altered in schizophrenia. Using in situ hybridization in subjects with schizophrenia and a comparison group, we detected increased expression of JWA and KIAA0302, molecules that regulate EAAT3 and EAAT4, respectively, in the thalamus in schizophrenia. In contrast, we did not find changes in the expression of transcripts for the EAAT2 and EAAT4 regulatory proteins GPS-1 and ARHGEF11. To address prior antipsychotic treatment in our schizophrenic subjects, we treated rats with haloperidol and clozapine for 4 weeks, and found changes in transcript expression of the EAAT-interacting proteins in clozapine-, but not haloperidol-, treated rats. These findings suggest that proteins associated with the regulation of glutamate reuptake may be abnormal in this illness, supporting the hypothesis of altered thalamic glutamatergic neurotransmission in schizophrenia.

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…The authors of one of the studies attributed this effect to the difference in the ages of the subjects included in the two studies (Eastwood and Harrison, 2005;Uezato et al, 2009). These findings, as well as the conclusions of the BrainCloud project, are consistent with reports of gene expression-specific associations with age of death (Eastwood and Harrison, 2005;Huerta et al, 2006;McCullumsmith et al, 2007;. Agerelated changes are likely not limited to transcripts.…”

Altered Vesicular Glutamate Transporter Expression in the Anterior Cingulate Cortex in Schizophrenia

“…Increased VGLUT1 mRNA could also be secondary to decreased cortical inhibitory tone, or a reaction to abnormal subcortical input to the ACC. Several studies have demonstrated abnormalities in GABAergic interneurons in the PFC, while others have found changes in regions with dense reciprocal innervation from the PFC, such as the thalamus [24,31,[43][44][45][46][47]. For example, transcript expression for VGLUT2 and glutaminase was increased in the dorsal thalamus in schizophrenia in a study using a different sample from the same brain bank we used in this study [24,46].…”

Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia

“…Some of the sensory and cognitive disturbances seen in schizophrenia are consistent with glutamatergic dysfunction of thalamic circuitry. Transcript expression studies of glutamatergic molecules in the thalamus by our laboratory have revealed many changes in this illness, including increased vesicular glutamate transporters, decreased NMDA receptor subunits and proteins involved in receptor trafficking, increased astrocytic EAATs 1 and 2, and increased EAAT interacting proteins (Clinton et al, 2006, Clinton and Meador-Woodruff, 2004, Huerta et al, 2006, Ibrahim et al, 2000, Smith et al, 2001a, Smith et al, 2001b. We have also demonstrated that glutamine synthetase transcript levels in the thalamus are increased in several nuclei, including those that project to the ACC and STG (Bruneau et al, 2005).…”