The limbic cortex in schizophrenia: focus on the anterior cingulate

Tamminga, Carol A.; Vogel, Michael W.; Gao, Xiaohan; Lahti, Adrienne C.; Holcomb, Henry H.

doi:10.1016/s0165-0173(99)00053-3

Cited by 88 publications

(38 citation statements)

References 55 publications

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“…Another possible explanation of the present finding could be based on the suggestion that a primary abnormality in the hippocampus in schizophrenia is associated with a reduced efferent hippocampal glutamate signal to ACC (see Tamminga et al 2000 for a review). It is therefore reasonable to hypothesize that a reduced efferent glutamatergic signal from the hippocampus would result in compensatory upregulation of AMPA and NMDA receptors in the ACC.…”

Section: Resultsmentioning

confidence: 93%

“…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.…”

mentioning

confidence: 99%

“…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 hippocampus to ACC (see Tamminga et al 2000 for a review). In addition, there is a growing evidence indicating abnormalities in other neurotransmitter systems in the ACC in schizophrenia including dopamine, GABA, and serotonin, that could contribute to an abnormal excitatory activity in this brain area (Benes 2000;Zavitsanou and Huang 2002).…”

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confidence: 99%

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

Zavitsanou

Ward

Huang

2002

Neuropsychopharmacology

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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...

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Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Zavitsanou

Ward

Huang

2002

Neuropsychopharmacology

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“…Due to its complexity, the amygdala has been less studied however, studies implicating this structure have begun to emerge, 43 including recent imaging studies that have reported a decrease in gray matter density in the amygdala of schizophrenic patients. 44 While many studies have suggested that abnormalities in the cingulate cortex contribute to the pathophysiology of schizophrenia (for review see Tamminga et al 45 ), this has not been consistently supported in the literature 37,38,46 Given the heterogeneity of schizophrenia, it is possible that abnormalities in the cingulate cortex may accompany certain subtypes of the disease (that have yet to be identified). Carter et al 47 have reported that in vivo functional imaging abnormalities in anterior cingulate are associated with neuropsychologic deficits, including attention.…”

Section: Discussionmentioning

confidence: 99%

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder

et al. 2003

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We previously demonstrated that apolipoprotein D (apoD) levels are elevated in the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects with schizophrenia and bipolar disorder compared to controls, suggesting a focal compensatory response to neuropathology associated with psychiatric disorders. We have now extended those studies by measuring apoD protein levels in additional brain regions from post-mortem samples of schizophrenic and bipolar disorder subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders.

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“…86 A follow-up study of similar design tested the regional associations of positive symptoms and showed that as long as patient volunteers were medication-free, there was a significant association between rCMRglu in the limbic cortex (ACC plus Hipp) and the magnitude of positive symptoms in the illness ( Figure 2); this correlation did not obtain when patients were medicated or with other symptom domains. 164 These studies allowed us to speculate that it was the limbic cortex which is associated with the positive symptoms of the illness, while the PFC cortex may support negative and/or cognitive symptoms.…”

Section: A Working Hypothesismentioning

confidence: 99%

Phenotype of schizophrenia: a review and formulation

2004

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The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

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The limbic cortex in schizophrenia: focus on the anterior cingulate

Cited by 88 publications

References 55 publications

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

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

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder

Phenotype of schizophrenia: a review and formulation

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