Frontal Cortical and Left Temporal Glutamatergic Dysfunction in Schizophrenia

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...

Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

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Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Meador‐Woodruff

2001

“…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). …”

Section: Resultsmentioning

confidence: 99%

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

Zavitsanou

Ward

Huang

2002

The anterior cingulate cortex is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Previous studies suggest abnormalities in the glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia patients. In the present study we used quantitative autoradiography to investigate the binding of [ 3 H]MK801, [ 3 H]L-␣ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA),Glutamate is the primary excitatory neurotransmitter in the human brain. Excitatory synaptic activity conveyed by glutamate is mediated by three pharmacologically defined subtypes of ionotropic glutamate receptors: N-methyl-D-aspartate (NMDA), D, L-␣ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate. The NMDA receptor comprises two subunits that are coded by genes designated NR1 and NR2A-D. Non-NMDA glutamate receptor subunits comprise GluR1-4, which are AMPA-preferring, and GluR5-7, KA1 and KA2, which are kainate preferring (Hollmann and Heinemann 1994).Pharmacological and biochemical data have suggested deficiency in glutamatergic transmission in schizo- Although it is usually the NMDA receptor that is implicated in schizophrenia, disturbances of any of the glutamate receptors could result in a condition that produces the appearance of an abnormally functioning NMDA receptor. For example, NMDA receptors are blocked by magnesium at physiological concentrations, and AMPA receptor-mediated depolarization of the membrane extrudes magnesium from the NMDA receptor complex (Reynolds and Miller 1990). Therefore, a pathological change in the function of non-NMDA receptors may affect the NMDA receptor.Given the possibility of glutamate receptor dysfunction in schizophrenia, the expression of ionotropic glutamate receptors has been studied in post-mortem brain of schizophrenia patients and abnormalities in glutamate receptors have been reported in many brain areas (reviewed by Meador-Woodruff and Healy 2000; see also Deakin and Simpson 1997). Some of these reports have not been replicated and have been done primarily in membrane preparations. These studies illustrate that the occurrence and nature of glutamate receptor abnormalities in schizophrenia can differ between brain regions.The anterior cingulate cortex (ACC; Brodmann's area 24) is localized within a gyrus on the media surface of each hemisphere, bordering on the corpus callosum. It receives projections from the amygdala (Vogt and Pandya 1987), thalamus (Vogt et al. 1979) and hippocampus (Vogt et al. 1979;Tamminga et al. 2000), possibly excitatory in nature. Abnormalities in glutamatergic neurotransmission have been reported in the ACC in schizophrenia. Recent studies using post-mortem human ACC indicate a dramatic increase in vertical glutamatergic axons in the superficial layers of ACC in schizophrenia (Benes 2000) and imaging studies suggest impaired activation of ACC in patients with schizophrenia during performance tasks, which could be attributed to a reduced efferent glutamatergic signal from the hippo...

“…The preponderance of these studies has detected complex and regionally specific alterations in ␣ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptor expression, especially in cingulate cortex and medial temporal lobe structures (Akbarian et al 1996;Aparicio-Legarza et al 1998;Deakin et al 1989;Eastwood et al 1997aEastwood et al , 1997bEastwood et al , 1995Grimwood et al 1999;Harrison et al 1991;Healy et al 1998;Humphries et al 1996;Ibrahim et al 2000;Kerwin et al 1988Kerwin et al , 1990Kornhuber et al 1989; MeadorWoodruff and Healy 2000;Nishikawa et al 1983;Noga et al 1997;Ohnuma et al 1998;Porter et al 1997;Sokolov 1998). Recently, such studies have been extended to other brain regions associated with limbic circuitry felt to be disturbed in psychiatric illnesses, including the striatum.…”

Section: Because Abnormalities Of Glutamatergic Neurotransmission In mentioning

confidence: 99%

Striatal Excitatory Amino Acid Transporter Transcript Expression in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

McCullumsmith

Meador‐Woodruff

2002

175

Because abnormalities of glutamatergic neurotransmission in psychiatric illness are likely not limited to glutamate receptor expression, we investigated expression of excitatory amino acid transporters (EAATs) in the striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic lateral sclerosis, and schizophrenia. In A growing literature suggests abnormal expression of ionotropic glutamate receptors in the brain in schizophrenia. The preponderance of these studies has detected complex and regionally specific alterations in ␣ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptor expression, especially in cingulate cortex and medial temporal lobe structures (Akbarian et al. 1996;Aparicio-Legarza et al. 1998;Deakin et al. 1989;Eastwood et al. 1997aEastwood et al. , 1997bEastwood et al. , 1995Grimwood et al. 1999;Harrison et al. 1991;Healy et al. 1998;Humphries et al. 1996;Ibrahim et al. 2000;Kerwin et al. 1988Kerwin et al. , 1990Kornhuber et al. 1989; MeadorWoodruff and Healy 2000;Nishikawa et al. 1983;Noga et al. 1997;Ohnuma et al. 1998;Porter et al. 1997;Sokolov 1998). Recently, such studies have been extended to other brain regions associated with limbic circuitry felt to be disturbed in psychiatric illnesses, including the striatum. Increased NMDA receptor binding at both the glycine/D-serine coagonist site and the intrachannel MK801 site was detected in the putamen, and increased CNQX (an AMPA/kainate antagonist) binding was detected in the caudate in schizophrenia (Aparicio-Legarza et al. (Arriza et al. 1993;Utsunomiya-Tate et al. 1996). The transporters have specific patterns of cellular localization: EAAT1 and EAAT2 have been localized to astroglia, whereas EAAT3 and EAAT4 are localized to neurons (Bar-Peled et al. 1997;Chaudhry et al. 1995;Furuta et al. 1997;Lehre et al. 1995;Milton et al. 1997;Rothstein et al. 1994;Sims and Robinson 1999;Yamada et al. 1996Yamada et al. , 1997. The best studied of the glutamate transporters, EAAT2 (called GLT-1 in the rat) accounts for ‫ف‬ 90% of forebrain glutamate reuptake in the rodent (Rothstein et al. 1996;Tanaka et al. 1997). The predominately glial expression of EAAT2 mRNA and protein, observed throughout the human brain, is highest in the forebrain (Bar-Peled et al. 1997;Milton et al. 1997). Similar to EAAT2, EAAT3 (called EAAC1 in the rat) protein expression in the human brain is detected in the frontal cortex and the hippocampus (Bar-Peled et al. 1997). EAAT3 is localized to both post-and presynaptic neuronal soma and is associated with ‫ف‬ 40% of rodent hippocampal glutamate transport (Rothstein et al. 1994). In contrast, levels of EAAT1 (called GLAST in the rat) and EAAT4 protein expression in the rodent central nervous system (CNS) are highest in the cerebellum in the Bergmann glia and Purkinje cell types, respectively, whereas human studies of EAAT1 protein expression indicate high levels in the f...