Cortical dopamine in schizophrenia: Strategies for postmortem studies

doi:10.1016/S0022-3956(96)00057-X

Journal of Psychiatric Research

Volume 31, Issue 2, March–April 1997, Pages 175-195

https://doi.org/10.1016/S0022-3956(96)00057-X Get rights and content

Abstract

Many of the symptoms of schizophrenia appear to involve dysfunction of the cognitive processes mediated by the neural circuitry of the cerebral cortex. The application of modern neuroscience techniques to the study of postmortem human brain specimens provides a powerful approach for exploring the manner in which cortical circuitry may be disrupted in schizophrenia. In this paper, we describe a strategy for the conduct of postmortem investigations of schizophrenia that involves (1) the use of a nonhuman primate model to guide the design and interpretation of studies in humans; (2) the detailed characterization of the normal organization of neural systems in the human cerebral cortex, and the range of inter-individual variations in that organization; and (3) the testing of specific hypotheses about the disruption of that organization in schizophrenia. The application of this strategy, and its value in overcoming some of the potential pitfalls of postmortem studies, is demonstrated in a series of investigations designed to test the hypothesis that dopamine neurotransmission is impaired in the entorhinal cortex in schizophrenia.

References (50)

M. Akil et al.
The distribution of tyrosine hydroxylase-immunoreactive fibers in the human entorhinal cortex
Neuroscience
(1994)
T. Becker et al.
MRI findings in medial temporal lobe structures in schizophrenia
European Neuropsychopharmacology
(1990)
F.M. Benes et al.
Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats
Brain Research
(1985)
B. Berger et al.
Major dopamine innervation of the cortical motor areas in the Cynomolgus monkey
A radioautographic study with comparative assessment of serotonergic afferents
Neuroscience Letters
(1986)
B. Berger et al.
Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates
Trends in Neuroscience
(1991)
B. Bogerts et al.
Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia
Psychiatry Research: Neuroimaging
(1990)
B. Bogerts et al.
Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia
Biological Psychiatry
(1993)
H. Braak et al.
The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases
Neuroscience Research
(1992)
G.T. Coker et al.
Analysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues
Molecular Brain Research
(1990)
A. Hitri et al.
Age-related changes in [³H]GBR 12935 binding site density in the prefrontal cortex of controls and schizophrenics
Biological Psychiatry
(1995)

D.A. Lewis et al.

The dopaminergic innervation of monkey prefrontal cortex: a tyrosine hydroxylase immunohistochemical study

Brain Research

(1988)

D.A. Lewis et al.

Four isoforms of tyrosine hydroxylase are expressed in human brain

Neuroscience

(1993)

M. Akil et al.

Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects

Archives of General Psychiatry

(1997)

M. Akil et al.

The dopaminergic innervation of monkey entorhinal cortex

Cerebral Cortex

(1993)

M. Akil et al.

The cytoarchitecture of the entorhinal cortex in schizophrenia

American Journal of Psychiatry

(1997)

L.L. Altshuler et al.

The hippocampus and parahippocampus in schizophrenic, suicide, and control brains

Archives of General Psychiatry

(1990)

S.E. Arnold et al.

Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia

Archives of General Psychiatry

(1991)

M.J. Beall et al.

Heterogeneity of layer II neurons in human entorhinal cortex

Journal of Comparative Neurology

(1992)

H. Beckmann et al.

Prenatal disturbances of nerve cell migration in the entorhinal region: a common vulnerability factor in functional psychoses?

Journal of Neural Transmission

(1991)

B. Berger et al.

Regional and laminar distribution of the dopamine and serotonin innervation in the macaque cerebral cortex: a radioautographic study

Journal of Comparative Neurology

(1988)

B. Bogerts et al.

Basal ganglia and limbic system pathology in schizophrenia

Archives of General Psychiatry

(1985)

H. Braak et al.

On areas of transition between entorhinal allocortex and temporal isocortex in the human brain

Normal morphology and lamina-specific pathology in Alzheimer's disease

Acta Neuropathologica

(1985)

A. Breier et al.

Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures

Archives of General Psychiatry

(1992)

T.J. Brozoski et al.

Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkeys

Science

(1979)

D.G. Daniel et al.

The effect of apomorphine on regional cerebral blood flow in schizophrenia

Journal of Neuropsychiatry

(1989)

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Schizophrenia is a disorder of higher order hierarchical processing
2009, Medical Hypotheses
Schizophrenia is a mental disorder in which the patient manifests with auditory hallucinations, paranoid or bizarre delusions, and disorganized speech and thinking. It is associated with significant social dysfunction. There are many hypotheses regarding schizophrenia. Most of these focus on schizophrenia as a manifestation of abnormalities from genetic [Mulle JG. Genomic structural variation and schizophrenia. Curr Psychiatry Rep 2008;10(2):171–7], viral [Fruntes V, Limosin F. Schizophrenia and viral infection during neurodevelopment: a pathogenesis model? Med Sci Monit 2008;14(6):RA71–7], neurochemical [e.g. dopamine (Lewis DA, Akil M. Cortical dopamine in schizophrenia: strategies for postmortem studies. J Psychiatr Res 1997;31(2):175–95) or interactions between neurotransmitters (Duncan GE, Sheitman BB, Lieberman JA. An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 1999;29(2):250–64)] or brain structural [Kotrla KJ, Weinberger DR. Brain imaging in schizophrenia. Annu Rev Med 1995;46:113–22] origins. Most of these hypotheses do not account for how or why these presumed causes lead to the manifestations of schizophrenia. We argue that brain structure and function is compatible with a hierarchical processing structure that forms the basis for perception and thought in healthy humans. We propose that perturbations of the types listed above lead to disruption of higher levels of perception and hierarchical temporal processing by the brain and that this constitutes the core deficit in schizophrenia.
We present evidence that this model explains many of the features of schizophrenia and we make a series of predictions about schizophrenia.
AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs
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Disturbances in glutamate neurotransmission are thought to be one of the major contributing factors to the pathophysiology of schizophrenia. In the dorsolateral prefrontal cortex (DLPFC), glutamate neurotransmission is largely mediated by AMPA receptors. Data regarding alterations of subunit expression in the brains of patients with schizophrenia remain equivocal. This may be due to differences in technique sensitivity, endogenous control selection for normalization of data, or effect of antipsychotic drug treatment in different cohorts of schizophrenia. This study attempted to address these issues by examining the expression of AMPA receptor subunits and splice variants in the DLPFC of two schizophrenia cohorts using quantitative PCR (qPCR) with normalization to the geometric mean of multiple endogenous controls. In addition, a non-human primate model of chronic antipsychotic drug administration was used to determine the extent to which the transcript expression may be altered by antipsychotic drug treatment in the primate DLPFC. AMPA receptor subunits and flip and/or flop splice variants were not significantly different in the DLPFC of schizophrenia subjects versus controls in either of the two cohorts. However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA. Expression of AMPA receptor splice variants was not significantly altered by antipsychotic drug administration. This is the first study to show that AMPA receptor subunit mRNAs in the primate DLPFC are altered by antipsychotic drug administration. Antipsychotic drug-induced alterations may help explain differences in human post-mortem studies regarding AMPA receptor subunit expression and provide some insight into the mechanism of action of antipsychotic drugs.
The human brain revisited: Opportunities and challenges in postmortem studies of psychiatric disorders
2002, Neuropsychopharmacology
Studies of the postmortem human brain have become an increasingly essential element of the effort to understand the neurobiology of psychiatric disorders, especially in light of advances in our knowledge of functional brain circuitry and the new opportunities to apply the approaches of genomics and proteomics. This Perspective reviews some of the opportunities afforded by investigations of the postmortem human brain, and offers suggestions for improving the quality of future studies through the use of well-characterized brain specimens, well-constructed experimental designs and well-controlled confounds.
Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects
2000, Biological Psychiatry
Citation Excerpt :
Current views of the role of dopamine (DA) in schizophrenia hold that a functional excess of DA in subcortical structures may coexist with a deficit in DA neurotransmission in the cerebral cortex (Davis et al 1991; Goldstein and Deutch 1992; Heritch 1990; Weinberger et al 1988). Indeed, previous reports suggestive of altered DA neurotransmission in the prefrontal cortex (PFC) of schizophrenic subjects (Daniel et al 1989, Daniel et al 1991; Meador-Woodruff et al 1997; Stefanis et al 1998) are supported by our recent finding of reductions in markers of DA axon density in this cortical region (Akil et al 1999); however, abnormalities of cortical DA neurotransmission in schizophrenia are unlikely to be restricted to the PFC. For example, the rostral entorhinal cortex (ERC), which receives a dense DA innervation in primates (Akil and Lewis 1993, 1994), has also been implicated as a site of dysfunction in schizophrenia (Arnold 1997; Harrison 1999; Lewis and Akil 1997). The ERC constitutes the rostral portion of the parahippocampal gyrus in the medial temporal lobe (Figure 1 ) and is reciprocally connected to multiple unimodal and polymodal sensory association areas of the cerebral cortex (Insausti et al 1987).
Background: We recently reported a laminar-specific reduction in the density of tyrosine hydroxylase (TH)-immunoreactive axons in the prefrontal cortex of subjects with schizophrenia. In this report, we extend these investigations to the entorhinal cortex (ERC), another candidate site of dysfunction in this disorder.
Methods: Using immunocytochemical techniques and blind quantitative analyses, we determined the density of TH-immunoreactive axons in the rostral subdivision of the ERC from seven matched pairs of schizophrenic and control subjects.
Results: The relative density of TH-labeled axons was significantly decreased by over 60% in layers 3 and 6, but not in layer 1, of the ERC in schizophrenic subjects. In contrast, in the prefrontal cortex of the same subjects, labeled axon density was significantly decreased by 62% only in layer 6. Furthermore, the length of TH-labeled axons did not differ between six matched pairs of nonschizophrenic psychiatric and control subjects in any layer of the ERC. Finally, the density of TH-labeled axons in the ERC of cynomolgus monkeys chronically treated with haloperidol was not reduced relative to control animals.
Conclusions: These findings reveal regional- and laminar-specific alterations in TH-immunoreactive axons that appear to be specific to the pathophysiology of schizophrenia.
Familial transmission of risk factors in the first-degree relatives of schizophrenic people
2000, Biological Psychiatry
Citation Excerpt :
In the medial temporal lobe, the area associated with the source of the P50 response, the hippocampal formation and associated parahippocampal neocortex, which include the entorhinal cortex, express receptors for dopamine (Meador-Woodruff et al 1994). Dopaminergic innervation of the entorhinal cortex is especially prominent, although it has been reported to be decreased in schizophrenia (Lewis and Akil 1997). The biological concomitant of increased dopaminergic neurotransmission at the single neuron level is an increase in sensitivity to neuronal stimuli (Johnson et al 1983).
Schizophrenia is a complex illness with multiple pathophysiologic factors that contribute to its psychopathology. One strategy to identify these factors is to observe them in isolation from each other, by characterizing their expression in the relatives of schizophrenic probands. By Mendel’s second law, each genetic factor should be independently distributed in a sibship, so that each can be observed by itself, uncomplicated by the general problems of the illness. Such independently distributed phenotypes are obviously useful for genetic analyses; however, they can also be considered together, to model how various brain dysfunctions may combine to produce psychoses. In addition to a sensory gating deficit linked to the α7-nicotinic acetylcholine receptor locus, schizophrenics and their families have a number of other deficits, including decreased hippocampal volume on magnetic resonance images and increased plasma levels of the dopamine metabolite homovanillic acid. Although such research is far from complete, a heuristic model combining a sensory gating deficit, decreased hippocampal neuron capacity, and increased dopaminergic neurotransmission is consonant with current understanding of the neuropsychology of schizophrenia.
Development, disease and degeneration in schizophrenia: A unitary pathophysiological model
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In recent years, several pathophysiological models of schizophrenia, i.e. the early and late brain neurodevelopmental and post-illness onset neurodegenerative models, have been proposed and theorists have often argued as if these explanations are mutually exclusive. We propose that all these mechanisms may interact cumulatively during successive critical ‘windows of vulnerability’ during brain development and during the early course of the illness to lead to the clinical manifestations of the illness. Early brain insults may lead to dysplasia of selective neural networks that account for the premorbid cognitive and psychosocial dysfunction seen in many patients. The onset of psychosis in adolescence may be related to an excessive elimination of synapses and secondarily, phasic dopaminergic overactivity. Following illness onset, these neurochemical alterations in relation to continuing untreated psychosis may lead to further neurodegenerative processes. A reduction in tonic glutamatergic neurotransmission and a phasic glutamatergic excess can potentially predispose to these processes and may have considerable explanatory power. This hypothesis is consistent with central characteristics of schizophrenia such as premorbid manifestations, adolescent onset, functional decline early in this illness, cognitive impairments, the role of dopamine and the role of genes and environment in pathophysiology. This ‘three hit’ model extends similar integrative conceptualization by other investigators and generates testable predictions of relevance to future pathophysiology and treatment research in schizophrenia.

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Cortical dopamine in schizophrenia: Strategies for postmortem studies

Abstract

Neuroscience

European Neuropsychopharmacology

Brain Research

Neuroscience Letters

Trends in Neuroscience

Psychiatry Research: Neuroimaging

Biological Psychiatry

Neuroscience Research

Molecular Brain Research

Biological Psychiatry

Brain Research

Neuroscience

Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects

Archives of General Psychiatry

The dopaminergic innervation of monkey entorhinal cortex

Cerebral Cortex

The cytoarchitecture of the entorhinal cortex in schizophrenia

American Journal of Psychiatry

The hippocampus and parahippocampus in schizophrenic, suicide, and control brains

Archives of General Psychiatry

Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia

Archives of General Psychiatry

Heterogeneity of layer II neurons in human entorhinal cortex

Journal of Comparative Neurology

Prenatal disturbances of nerve cell migration in the entorhinal region: a common vulnerability factor in functional psychoses?

Journal of Neural Transmission

Regional and laminar distribution of the dopamine and serotonin innervation in the macaque cerebral cortex: a radioautographic study

Journal of Comparative Neurology

Basal ganglia and limbic system pathology in schizophrenia

Archives of General Psychiatry

On areas of transition between entorhinal allocortex and temporal isocortex in the human brain

Normal morphology and lamina-specific pathology in Alzheimer's disease

Acta Neuropathologica

Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures

Archives of General Psychiatry

Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkeys

Science

The effect of apomorphine on regional cerebral blood flow in schizophrenia

Journal of Neuropsychiatry