Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Abstract

A growing literature suggests glutamatergic dysfunction in schizophrenia. Perhaps the strongest evidence for glutamatergic involvement in this illness is that dissociative anesthetics, especially phencyclidine and ketamine, can cause a schizophreniform psychosis in normal humans, and worsen psychotic symptoms in persons with schizophrenia (Itil et al. 1967;Javitt and Zukin 1991;Krystal et al. 1994;Lahti et al. 1995;Luby et al. 1962). These drugs are uncompetitive inhibitors of the NMDA subtype of glutamate receptor, suggesting that schizophrenia may be associated with decreased NMDA receptor activity (Javitt and Zukin 1991;Carlsson and Carlsson 1990). Further, facilitators of NMDA receptor activity have been shown to improve psychotic symptoms. Since direct agonists of this receptor are neurotoxic, other therapeutic strategies have been used to enhance NMDA receptor activity. Agonists at the glycine co-agonist site of the NMDA receptor have been found to improve negative psychotic symptoms, providing additional support for diminished NMDA receptor activity in schizophrenia (Goff et al. 1995;Goff et al. 1999;Heresco-Levy et al. 1999;Javitt et al. 1994).In addition to the NMDA subtype, however, there NO . 5 are additional families of cation-selective ionotropic glutamate receptors, the AMPA and kainate subtypes. Although the NMDA receptor is the subtype of glutamate receptor usually implicated in schizophrenia, the other ionotropic glutamate receptors also may be abnormal in this illness; abnormalities. While a growing literature suggests abnormal expression of both NMDA and AMPA receptors in the brain in schizophrenia (reviewed in Meador-Woodruff and Healy 2000), much less is known about potential abnormalities of the kainate receptor in this illness. The ionotropic glutamate receptors share a common structural motif, and are each composed of four or five family-specific subunits that form ligandgated ion channels (Hollmann and Heinemann 1994). Kainate receptors are composed of the low affinity gluR5, gluR6, and gluR7 subunits, and the high affinity KA1 and KA2 subunits (Hollmann and Heinemann 1994). The gluR5, gluR6, and gluR7 subunits assemble into homomeric complexes, or heteromerically coassemble with KA1 and KA2, resulting in receptors with distinct pharmacological properties, suggesting that subunit composition, at least in part, determines the functional properties of the kainate receptor (Lerma 1998).Only several studies have examined the kainate-associated subunits in schizophrenic brain. Decreased expression of gluR6 and KA2 mRNA were noted in several hippocampal regions, although gluR6 mRNA was not found to be changed in the cerebellum in schizophrenia in this same study (Porter et al. 1997). A recently published study suggested that gluR7 and KA1 subunit transcripts are decreased in the superior frontal gyrus in schizophrenics, similar to decreases also noted by this investigator for some of the subunits associated with the AMPA and NMDA receptors (Sokolov 1998). Only one study to date has examine...

Cortical Glutamatergic Markers in Schizophrenia

“…Our finding of decreased cortical kainate receptors in BA 9 partially replicates another study, which showed a decrease in kainate binding in the prefrontal cortex (BA 9,11,32,and 46) in schizophrenia (Meador-Woodruff et al, 2001a). However, this earlier study found decreases in KA2 mRNA and increased GluR7 mRNA in tissue from the same subjects, which contrasts with our finding of decreased GluR5 mRNA.…”

“…This is demonstrated by studies that have investigated multiple cortical regions and shown an increase in the NMDA receptor in BA 22 but not BA 10 (Nudmamud and Reynolds, 2001) from subjects with the disorder. Similarly, decreases in kainate receptors in the prefrontal but not the occipital cortex (Meador-Woodruff et al, 2001a) have been reported. Thus, to avoid introducing cortical regional variation in changes in glutamate receptors as a confounding variable in discussion of our study in BA 9, our findings will be compared to other studies in either this CNS region or in the dorsolateral prefrontal cortex (DLPFC; BA 9 and 46) from subjects with schizophrenia.…”

“…There are numerous possible explanations for the variation in results on the study of kainate, and other glutamatergic, receptors in the cortex from subjects with schizophrenia, for example, smaller cohorts (eg n ¼ 8 in the previous study from one of our laboratories), the use of different levels of diagnostic criteria (eg schizophrenia vs catatonic, disorganized, paranoid, residual, and undifferentiated forms of the disorder; American Psychiatric Association 2000), differences in the genetic homogeneity of the diagnostic cohorts (eg Nishikawa et al, 1983;Toru et al, 1988, mainly Japanese), and different tissue collection parameters (eg average age of subjects; Meador-Woodruff et al, 2001a). It is clearly difficult to ascertain the impact of these variables.…”

Selective Alterations in Ionotropic Glutamate Receptors in the Anterior Cingulate Cortex in Schizophrenia

“…In the present study no changes in [ 3 H]kainate binding were observed in the ACC between the schizophrenia and control groups. Interestingly, kainate receptor binding has been reported to be elevated in multiple cortical areas in schizophrenia (Deakin et al 1989;Nishikawa et al 1983) and decreased in prefrontal cortex (Meador-Woodruff et al 2001). …”

Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia

“…Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence. [8][9][10][11] We performed an association study between the ser310ala GRIK3 polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504).…”