Recent Advances in the Neuropathology of Schizophrenia

Bogerts, Bernhard

doi:10.1093/schbul/19.2.431

Cited by 281 publications

(115 citation statements)

References 161 publications

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“…A confluence of data from histopathological, neurochemical, in vivo imaging, and neuropsychological studies point to abnormalities of neuronal circuitry in corticolimbic regions particularly the prefrontal and cingulate cortices, and structures of the temporal lobe including the hippocampal formation. [88][89][90][91] Despite several compelling and interesting theories, the precise nature of these circuitry abnormalities is unknown, and further progress has been hampered by inconsistencies and poor replication of the findings. These problems are due in part to methodological issues and inadequate sample availability, but more importantly they bespeak the heterogeneity of the disease.…”

Section: Modeling Mechanisms: Defining the Questionsmentioning

confidence: 99%

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Pearce

2001

Mol Psychiatry

135

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The task of defining schizophrenia pathogenesis has fascinated and frustrated researchers for nearly a century. In recent years, unprecedented advances from diverse fields of study have given credence to both viral and developmental theories. This review considers possible mechanisms by which viral and developmental processes may interact to engender schizophrenia. Many of the current controversies in schizophrenia pathogenesis are reviewed in light of the viral hypothesis, including: epidemiological findings and the role of a genetic diathesis, phenotype heterogeneity, abnormalities in excitatory and inhibitory neurotransmitter systems, anomalous cerebral latereralization, and static vs progressive disease. The importance of animal models in elucidating the impact of viral infections on developing neurons is illustrated by recent studies in which neonatal rats are infected with lymphocytic choriomeningitis virus in order to examine alterations in hippocampal circuitry. Finally, consideration is given to a new hypothesis that some cases of schizophrenia could be instigated by a viral infection that disrupts developing inhibitory circuits, consequently unleashing glutamatergic neurotransmission leading to selective excitotoxicity, and a degenerative disease course. Molecular Psychiatry (2001) 6, 634-646.

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Section: Modeling Mechanisms: Defining the Questionsmentioning

confidence: 99%

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Pearce

2001

Mol Psychiatry

135

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“…The neurodevelopmental theory is based on several abnormal findings in patients with schizophrenia: abnormal architectural arrangements of individual nerve cells, cell clusters, or cortical layers (Bogerts, 1993), neurons that are misplaced, mis-sized, and disorganized (Harrison, 1997), absence of normal cerebral structural asymmetry (Crow et al, 1989), relative stability of cognitive dysfunction (Rund, 1998), absence of gliosis (Falkai et al, 1999), and premorbid behavioral abnormalities (Jones et al, 1994). All these observations are consistent with a disorder of prenatal brain development, and argue against the notion that schizophrenia is a progressive degenerative brain disorder (Bogerts, 1993;Mjellem and Kringlen, 2001;Weinberger, 1995;Harrison, 1995Harrison, , 1997. There is, consequently, a robust clinical rationale to support the validation of a neurodevelopmental model of schizophrenia (Lillrank et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Andersen

Pouzet

2004

Neuropsychopharmacol

119

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It has been suggested that perinatal treatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) induces transient neurodegeneration in the limbic and cortical structures of rats. Since dysfunction of these structures is associated with cognitive deficits in patients with schizophrenia, we studied the effects of subchronic treatment with PCP in perinatal rats with respect to spatial reference, reversal, and spatial working memories using the Morris water maze task in adulthood. In addition, we investigated the effect of D-serine, which has clinical relevance for the treatment of cognitive deficits in patients with schizophrenia. Our goal was to develop a neurodevelopmental model with predictive validity for the cognitive dysfunction described in patients with schizophrenia. Male and female Sprague-Dawley rats were treated with either saline or PCP (8.7 mg/kg s.c.) on days 7, 9, and 11, postnatal, and the long-term behavioral effects were investigated in adulthood. Male PCP-treated rats were slightly impaired during the spatial reference memory task, but strongly impaired during the reversal and spatial working memory tasks. Female rats were not significantly affected by this treatment. This cognitive deficit was reversed by chronic treatment with D-serine. We suggest that this model mimics some of the cognitive deficits of patients with schizophrenia and might be appropriate for the screening of putative antipsychotic agents for the treatment of these cognitive deficits.

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“…Thus, these excitatory alterations could be used to delineate the neuronal circuits that, when functioning abnormally, produce psychotic behavior. Because of the important role of the EC in the processing of sensory input (Jones 1993) and disturbances in the neuronal organization and activity repeatedly observed in the EC neurons in schizophrenic brains (Falkai et al 1988;Arnold et al 1991;Bogerts 1993;Jakob and Beckmann 1994;Silbersweig et al 1995), caudal EC is a strong candidate for the brain area that is affected in schizophrenia. The relatively large number of affected neurons in the cEC and the wealth of information concerning the connectivity and physiology of the entorhinal-hippocampal system render this brain area a good candidate for a model system.…”

mentioning

confidence: 99%

“…Analysis of post-mortem material have suggested that brains of schizophrenic patients may display cytoarchitectonic disturbances in the entorhinal cortex (Falkai et al 1988;Arnold et al 1991;Bogerts 1993;Jakob and Beckmann 1994). CT scans of brains of schizophrenic patients have consistently demonstrated loss of gray matter in parahippocampal gyrus (Roberts 1990).…”

mentioning

confidence: 99%

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

Väisänen

Lindén

Lakso

et al. 1999

Neuropsychopharmacology

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We have characterized excitatory effects of non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine in the rat entorhinal cortex and in cultured primary entorhinal cortical neurons using expression of immediate early gene c-fos as an indicator. NMDA receptor antagonists produced a strong and dose-dependent increase in c-fos mRNA and protein expression confined to neurons in the layer III of the caudal entorhinal cortex. Induction of c-fos mRNA is delayed and it is inhibited by antipsychotic drugs. Cultured entorhinal neurons are killed by high doses of MK-801 and PCP but c-fos expression is not induced in these neurons indicating that this in vitro model does not fully replicate the in vivo effects of PCP-like drugs in the entorhinal cortex. Excitatory effects of the NMDA receptor antagonists may be connected with the psychotropic side effects of these drugs and might become a useful modelNMDA receptor antagonists, such as phencyclidine, ketamine, and MK-801 (dizocilpine) produce in humans psychotogenic side effects which clinically closely resemble schizophrenia and are characterized by distorted body image, hallucinations, vivid dreams, and delirium (Johnson and Jones 1990;Javitt and Zukin 1991). Ketamine also frequently induces psychotic "emergence reactions" in adults (Krystal et al. 1994). Because of these parallels between the psychotomimetic state produced by the NMDA receptor antagonists and schizophrenia, PCP-induced psychosis has widely been used as an experimental model of schizophrenia (Javitt and Zukin 1991).In a series of pioneering studies, Olney and coworkers demonstrated that NMDA receptor antagonists produce reversible neurotoxic effects in neurons in the posterior cingulate and retrosplenial cortices (RSC) of rat brain (Olney et al. 1989(Olney et al. , 1991 Farber 1995a, 1995b). These effects are characterized by reversible intracellular vacuolization (Olney et al. 1989) and induction of mRNAs for c-fos (Dragunow and Faull 1990;Hughes et al. 1993;Näkki et al. 1996), heat shock protein 70 (HSP70) (Sharp et al. 1991(Sharp et al. , 1994Näkki et al. 1995), and brain-derived neurotrophic factor (BDNF) Hughes et al. 1993). Induction of cfos and BDNF is typically observed in activated neurons and we therefore tentatively call these effects "ex- citatory" to distinguish them from the prevention of excitation, which is the typical effect of NMDA receptor antagonists in other brain areas. These excitatory actions may be connected with the psychotomimetic side effects produced by PCP-like drugs Farber 1995a, 1995b). We have previously observed that MK-801 increases mRNA for BDNF not only in the retrosplenial cortex but also in the entorhinal cortex (EC) . EC is the input and output station of the information going to and coming from the hippocampus (Jones 1993;Amaral and Witter 1995). It is thought that the EC-hippocampus loop is very important in the processing of sensory information and defects in its normal function might produce cognitive disturbances (Jones 1993). Therefore, neurons i...

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Recent Advances in the Neuropathology of Schizophrenia

Cited by 281 publications

References 161 publications

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

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