Loss of Glial Glutamate and Aspartate Transporter (Excitatory Amino Acid Transporter 1) Causes Locomotor Hyperactivity and Exaggerated Responses to Psychotomimetics: Rescue by Haloperidol and Metabotropic Glutamate 2/3 Agonist

Karlsson, Rose−Marie; Heilig, Markus; Holmes, Andrew

doi:10.1016/j.biopsych.2008.05.001

Cited by 89 publications

(83 citation statements)

References 23 publications

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“…More specifically, these studies revealed a link between a high-risk GRM3 allele and reduced expression of glial glutamate transporter. Although there is not much further evidence in support of this hypothesis, a genetic silencing of glial transporter expression in mice resulted in the behavioral abnormalities that are typically observed after the treatment with psychotomimetic drugs (Karlsson et al, 2008). The most intriguing is perhaps that these behaviors were effectively antagonized by the stimulation of mGlu2/3 receptors.…”

Section: Mglu2/3 Receptor Agonistsmentioning

confidence: 99%

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Marek

Behl²,

Bespalov³

et al. 2009

Mol Pharmacol

139

115

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Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytrypatmine 2A receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved. Dopamine and serotonin, as opposed to emerging interest in glutamate, played a dominant role during the formative years of modern psychopharmacology when thinking about the pathophysiology and treatment of schizophrenia. Models derived from studying the behavioral effects of amphetamine and serotonergic hallucinogens were emphasized (Table 1). The seminal observations by Arvid Carlsson and his colleagues in the late early 1960s that first postulated functional dopamine receptor blockade as a necessary therapeutic action by the phenothiazine and butyrophenone structural classes set the stage for our current mechanistic understanding of all antipsychotic drugs currently used today (Carlsson and Lindqvist, 1963). The emergence of in vitro receptor binding and positron emission topography receptor occupancy studies in healthy volunteers and patients identified dopamine D2 receptor Article, publication date, and citation information can be found at

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Section: Mglu2/3 Receptor Agonistsmentioning

confidence: 99%

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Marek

Behl²,

Bespalov³

et al. 2009

Mol Pharmacol

139

115

View full text Add to dashboard Cite

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“…Furthermore, previous research indicates antipsychotics act pharmacologically on the glutamate system resulting in molecular as well as physiological consequences and thereby may influence therapeutic outcome [Riva et al, 1997;Tascedda et al, 2001;Goff et al, 2002]. Karlsson and group reported excessive glutamatergic signaling in the prefrontal cortex that promotes presynaptic glutamate modulation mGlu2/3 receptors activation suggesting these receptor may exert antipsychotic efficacy [Karlsson et al, 2008].…”

Section: Introductionmentioning

confidence: 98%

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

Kaur

Jajodia

Grover

et al. 2014

American J of Med Genetics Pt B

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Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions.

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“…Such a selective loss of GLT-1/EAAT-2 occurs in patients suffering from ALS (Rothstein et al 1995) and was further noted in mice over-expressing mutant huntingtin (Behrens et al 2002;Bradford et al 2009). Finally, recent studies pinpointed GLAST/EAAT-1 as a putative risk factor for schizophrenia (Karlsson et al 2008(Karlsson et al , 2009Walsh et al 2008).…”

Section: Discussionmentioning

confidence: 98%

Transcriptional Regulation of the GLAST/EAAT-1 Gene in Rat and Man

et al. 2012

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Various acute and chronic brain diseases result in disturbed expression of the glial glutamate transporters, GLAST/EAAT-1 and GLT-1/EAAT-2, and subsequent secondary neuronal cell death. The idea that glutamate-induced brain damage can be prevented by restoring glutamate homeostasis in the injured brain, focussed previous efforts on identifying the network controlling astrocytic glutamate transport. Since most of this work was performed with rat astrocytes, we now sought to compare the transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. Reporter gene assay demonstrated that the human GLAST/EAAT-1 promoter comprises the 2.3 kb region immediately flanking the 5'-end of the human GLAST/EAAT-1 gene. Cloning of the previously unknown promoter of rat GLAST/EAAT-1 gene demonstrated maximal reporter gene activity with a sequence comprising the 1.5 kb region flanking the 5'-end of the gene as well as non-coding exon 1, and intron 1-2. Although the promoter regions from both species lacked sequence homology, they contained numerous identical consensus motifs. In human promoter constructs, dbcAMP, PACAP, EGF, and TGFα, which represent potent stimulators of endogenous GLAST/EAAT-1 expression, only further increased reporter gene activity in the presence of the GLAST/EAAT-1 3'-UTR. By contrast, the rat GLAST/EAAT-1 3'-UTR only mediated the stimulatory increases of dbcAMP. Moreover, the GLAST/EAAT-1 3'-UTR repressed constitutive GLAST/EAAT-1 expression in man, but enhanced GLAST/EAAT-1 transcription in rat. Together, our findings suggest the existence of close functional similarities of the GLAST/EAAT-1 promoter regions in man and rat and further point to a species-specific function of the GLAST/EAAT-1 3'-UTR in constitutive and regulated GLAST/EAAT-1 expression.

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Loss of Glial Glutamate and Aspartate Transporter (Excitatory Amino Acid Transporter 1) Causes Locomotor Hyperactivity and Exaggerated Responses to Psychotomimetics: Rescue by Haloperidol and Metabotropic Glutamate 2/3 Agonist

Cited by 89 publications

References 23 publications

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

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

Transcriptional Regulation of the GLAST/EAAT-1 Gene in Rat and Man

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