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

Abstract

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...

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

“…As compared to NR1 and other subunits, a relative increase of NR2A subunits was seen in frontal and occipital cortex (mRNA), of NR2B subunits in temporal cortex (binding) and of NR2D subunits (mRNA) in prefrontal cortex (Akbarian et al 1996;Grimwood et al 1999;Dracheva et al 2001;Woo et al 2004). Despite these changes, binding of radioligands to Glycine B sites was increased in several cortical areas; further, no consistent pattern of changes has been seen with radioligands at recognition sites for glutamate (Ishimaru et al 1994;Grimwood et al 1999;Millan 2002;Zavitsanou et al 2002;Van Berckel 2003). Thus, while cortical NMDA receptors are affected in schizophrenia, there is no clear evidence for a reduction in their activity.…”

Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

“…It should be noted that despite no pathological alteration of mGluR2/3 and mGluR5 binding sites in the present study, the ACC remains highly involved in these pathologies as alterations of various neurotransmitters and their associated receptors have been reported in this brain region. 3,7,[40][41][42] Although our study provides valuable information on these binding sites in psychiatric pathology, additional studies examining binding specifically to membranous mGluR2/3 and mGluR5 and the affinity of novel mGluR2/3-and mGluR5-targeting drugs for these receptors in psychiatric disorders will provide valuable insight into the effectiveness of these drugs in the patient. 33 One confound of postmortem studies in neuropsychiatric disorders, is the presence of comorbid substance abuse, especially alcohol and drug abuse, or at least substantially higher alcohol 43 and illicit drug 44 intake in patients with psychiatric disorders.…”

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

“…In agreement with our finding of increased NR1 C2 0 expression, selective increase in NMDA receptor binding in the ACC has been reported in schizophrenia, which was hypothesized to be a cellular response to impaired glutamatergic neurotransmission. 78 Implications for glutamatergic circuitry of the frontal cortex in schizophrenia Glutamatergic signaling in the frontal cortex is exerted principally by pyramidal neurons. 43 Despite the fact that different cell types in all cortical layers express NMDA receptors, 79 pyramidal cells account for approximately 70% of NMDA receptor expression in the frontal cortex.…”