RETRACTED: Dysregulated glutamate and dopamine transporters in postmortem frontal cortex from bipolar and schizophrenic patients

Abstract

Background Dysregulated glutamate, serotonin and dopamine neurotransmission has been reported in bipolar disorder (BD) and schizophrenia (SZ), but the underlying mechanisms of dysregulation are not clear. We hypothesized that they involve alterations in excitatory amino acid transporters (EAATs), the serotonin reuptake transporter (SERT), and the dopamine reuptake transporter (DAT). Methods To test this hypothesis, we determined protein and mRNA levels of EAAT subtypes 1–4, of the SERT and of the DAT in postmortem frontal cortex from BD (n=10) and SZ (n=10) patients and from healthy control (n=10) subjects. Results Compared to control levels, protein and mRNA levels of EAAT1 were increased significantly in cortex from both BD and SZ patients. EAAT2 protein and mRNA levels were decreased significantly in BD but not in SZ cortices. EAAT3 and EAAT 4 protein and mRNA levels were significantly higher in SZ but not in BD compared with control. DAT protein and mRNA levels were decreased significantly in both BD and SZ cortex. There was no significant change in SERT expression in either BD or SZ. Conclusions The altered EAATs and DAT expression could result in altered glutamatergic and hyperdopaminergic function in BD and SZ. Differently altered EAATs involved in glutamatergic transmission could be therapeutic targets for treating BD and SZ.

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

“…Evidence of dysfunction of astrocytes in the LC region in individuals with MDD include reduced expression of SLC1A3, SLC1A2 and GFAP; lower GFAP protein levels; and reduced density of GFAP-positive astrocytes. Altered expression of glutamate transporter genes has been reported previously in a number of studies of neurodegenerative and psychiatric diseases, [32][33][34] including MDD. 20,35 The present study provides direct evidence of astrocyte pathology in the cell body region of a monoamine neurotransmitter, indicating that glia cell abnormalities reported in more superior/rostral brain regions in MDD 16,19 extend to the brainstem and may contribute to pathology of mono amine systems.…”

GBR 12909 administration as an animal model of bipolar mania: time course of behavioral, brain oxidative alterations and effect of mood stabilizing drugs

“…Furthermore, we expanded the predictive validity of the model by the determination of Li preventive effects. Numerous findings from clinical studies highlight the importance of DAT in BD pathophysiology: i) a singlenucleotide polymorphism (SNP) in the rs27072 affecting DAT mRNA expression and translation was significantly associated with BD (Pinsonneault et al 2011) as well as the presence of multiple variants in DAT1 was noticed to convey susceptibility to BD (Greenwood et al 2006); ii) a decrease in DAT mRNA levels was demonstrated in the postmortem frontal cortex of BD patients as compared to healthy controls (Rao et al 2012) and iii) significant lower DAT availability relative to healthy controls was observed in the bilateral dorsal caudate of unmedicated BD patients that underwent PET imaging with the DAT-selective radiotracer [(11) C]CFT and a structural magnetic resonance imaging (MRI) scan (Anand et al 2011).…”

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

“…Similar to addiction, disruptions in glutamate homeostasis linked to schizophrenia are not restricted to changes in system x c Ϫ but also appear to involve changes in the activity of excitatory amino acid transporters (Bauer et al, 2008;Rao et al, 2012). Given the role of EAATs to compartmentalize glutamate into functionally distinct pools (e.g., synaptic, extrasynaptic), it is SYSTEM X C Ϫ AND DISEASE possible that receptors located in the synapse or in the extrasynaptic compartment are being stimulated by glutamate diffusing across microdomains.…”